Opioid abuse deterrent dosage forms

ABSTRACT

Described herein are oral abuse deterrent pharmaceutical compositions, methods for making the same, and methods for treating pain by administering the pharmaceutical composition to a subject in need thereof. In particular, an oral abuse deterrent pharmaceutical composition comprising a soft capsule and a controlled release matrix comprising oxycodone are described.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent ApplicationNo. 62/238,385, filed on Oct. 7, 2015, and U.S. Provisional PatentApplication No. 62/310,383, filed on Mar. 18, 2016, each of which areincorporated herein in its entirety by express reference thereto. Thisapplication is related to U.S. patent application Ser. No. 15/285,814having the same title and contemporaneously filed on Oct. 5, 2016.

TECHNICAL FIELD

Described herein are oral abuse deterrent controlled releasepharmaceutical compositions and methods for making the same. Inparticular, an oral abuse deterrent controlled release pharmaceuticalcomposition comprising a soft capsule and an abuse deterrent controlledrelease matrix comprising an active pharmaceutical ingredient aredescribed.

BACKGROUND

Increased attention has been drawn to the recreational use and abuse ofprescription pharmaceutical compositions. The abuse, or non-medicinaluse, of prescription pharmaceutical compositions is an increasingproblem. Accordingly, preventing the abuse of prescriptionpharmaceuticals through the development of abuse deterrentpharmaceutical compositions has become a high public health priority forthe U.S. Food and Drug Administration (FDA). Prescription pharmaceuticalcompositions that are typically misused or abused fall, primarily, intothree groups: (1) opioids prescribed for pain; (2) Central NervousSystem (CNS) depressants prescribed for anxiety or sleep problems; and(3) stimulants, prescribed, for example, for attention deficithyperactivity, narcolepsy, or obesity.

Methods for abusing prescription pharmaceutical compositions are variedand can include, for example, extraction, boiling, melting,volatilization, physical tampering (e.g., grinding, grating, crushing,etc.), or direct administration. For purposes of abuse, methods ofadministering active drug substances obtained from prescriptionpharmaceutical compositions or of the pharmaceutical compositionsthemselves are similarly diverse and include, for example, injection,smoking, snorting, swallowing, sublingual or buccal administration,chewing, or administration as an anal or vaginal suppository.Alcohol-induced “dose dumping,” i.e., the rapid release of activepharmaceutical ingredients in the presence of a solvent such as ethanol,is also an abuse concern and safety issue. Other methods include rapidextraction under aqueous boiling conditions.

There are a number of strategies for preventing the abuse ofpharmaceuticals. Physical and chemical barriers can prevent theextraction of the drug or change the form of the drug making it lesslikely to be abused. Combinations of agonists and antagonists can beused, wherein the antagonist is only released upon product manipulationor tampering. Another strategy is to use aversive compounds that producean unpleasant effect when the dosage form is tampered with. In addition,prodrugs can be used, which are only changed into the active form of thedrug in the gastrointestinal tract. The pharmaceutical industry isutilizing these strategies to develop abuse-deterrent pharmaceuticalcompositions in order to reduce the potential for misuse of prescriptionpharmaceutical compositions.

Accordingly, there is a need for abuse deterrent pharmaceuticalcompositions that have controlled release properties.

SUMMARY

Described herein are pharmaceutical compositions comprising abusedeterrent controlled release matrices comprising active pharmaceuticalingredients. The matrix is structured to prevent extraction of theactive pharmaceutical ingredients. Specifically, the matrix formulationsdescribed herein minimize the likelihood of tampering, “dose dumping,”or the extraction of active pharmaceutical ingredients from thecomposition. In particular, there is a need for formulations that areresistant to active pharmaceutical ingredient extraction under boilingconditions.

One embodiment described herein is an oral abuse deterrentpharmaceutical composition comprising a tamper resistant controlledrelease matrix, wherein the tamper resistant controlled release matrixcomprises a means for preventing the crushing, grating, grinding,cutting, solvating, or dissolving of the tamper resistant controlledrelease matrix comprising one or more active pharmaceutical ingredients.

Another embodiment described herein is an abuse deterrent oralpharmaceutical composition comprising a tamper resistant controlledrelease composition comprising: (a) one or more flowability enhancers;(b) one or more release modifiers; and (c) one or more activepharmaceutical ingredients; wherein the matrix is resistant totampering.

One embodiment described herein is a pharmaceutical compositioncomprising: (a) one or more flowability enhancers; (b) one or morerelease modifiers; and (c) one or more active pharmaceuticalingredients. In one aspect, the composition further comprises one ormore antioxidants. In another aspect, the composition further comprisesone or more viscosity modifiers. In another aspect, the flowabilityenhancer comprises about 35% to about 70% of the composition by mass. Inanother aspect, the release modifier comprises about 20% to about 50% ofthe composition by mass. In another aspect, the active pharmaceuticalingredient comprises about 0.5% to about 35% of the composition by mass.In another aspect, the antioxidant comprises about 0.05% to about 0.5%of the composition by mass. In another aspect, the viscosity modifiercomprises about 0.5% to about 10% of the composition by mass. In anotheraspect, the ratio of the active pharmaceutical ingredient mass to thecomposition mass comprises a range of about 1:1000 to about 1:3. Inanother aspect, a ratio of release modifier to flowability enhancer isabout 1:2. In another aspect, a ratio of active pharmaceuticalingredient to release modifier comprises a range of about 1:1 to about1:20. In another aspect, the flowability enhancer comprises a non-ionicsurfactant, an anionic surfactant, a zwitterionic surfactant, a cationicsurfactant, or a combination thereof. In another aspect, the flowabilityenhancer comprises a non-ionic surfactant. In another aspect, theflowability enhancer comprises a hydrophilic lipophilic balance of lessthan about 5. In another aspect, the flowability enhancer comprises amedium chain mono-, di-, or tri-glyceride; or a liquid lipophilicvehicle. In another aspect, the flowability enhancer comprises glycerylmonocaprylate, glyceryl monocaprylcaprate, glyceryl monolinoleate, oleicacid, or a combination thereof. In another aspect, the release modifiercomprises polyethylene oxide, a carboxyvinyl polymer, or a combinationthereof. In another aspect, the release modifier comprises apolyethylene oxide having a molecular weight (M_(v)) of about 1,000,000;about 2,000,000; about 3,000,000; about 4,000,000; about 5,000,000;about 6,000,000; about 7,000,000; about 8,000,000; about 9,000,000; orabout 10,000,000. In another aspect, the release modifier comprises apolyethylene oxide having a molecular weight (M_(v)) of about 4,000,000.In another aspect, the viscosity modifier comprises polyvinylpyrrolidone, ethylcellulose, or a combination thereof. In anotheraspect, the antioxidant comprises alpha-tocopherol, beta-tocopherol,gamma-tocopherol, delta-tocopherol, butylated hydroxyanisole (BHA),butylated hydroxytoluene (BHT), citric acid, ascorbic acid, carnosicacid, carnosol, rosmanol, epirosmanol, isorosmanol, methyl carnosate,rosmarinic acid, eugenol, eugenyl acetate, clove bud extract, methanolicextract, epigallocatechin gallate, epicatechin gallate,epigallocatechin, epicatechin, or a combination thereof. In anotheraspect, the composition forms an elastic, semi-solid composition afterbeing heated at a temperature of about 50° C. to about 80° C. for a timeperiod of about 10 min to about 180 min and then cooling the compositionto room temperature. In another aspect, the active pharmaceuticalingredient comprises an opioid agonist. In another aspect, the activepharmaceutical ingredient comprises oxycodone, hydrocodone, oxymorphone,hydromorphone, morphine, codeine, methadone, fentanyl, tapentadol,tramadol, meperidine, propoxyphene, flunitrazepam, barbiturates, amytal,nembutal, seconal, phenobarbital; benzodiazepines, zolpidem, zaleplon,eszopiclone, amphetamines, methylphenidate, a salt thereof, or acombination thereof. In another aspect, the active pharmaceuticalingredient comprises oxycodone or a pharmaceutically acceptable saltthereof. In another aspect, the active pharmaceutical ingredientcomprises oxycodone hydrochloride or oxycodone myristate. In anotheraspect, the active pharmaceutical ingredient comprises oxycodonehydrochloride comprising >25 ppm of 14-hydroxycodeinone. In anotheraspect, the active pharmaceutical ingredient comprises about 5 mg toabout 120 mg of oxycodone hydrochloride. In another aspect, the activepharmaceutical ingredient comprises about 5 mg, about 10 mg, about 15mg, about 20 mg, about 30 mg, or about 40 mg of oxycodone hydrochloride.

In one embodiment described herein, the composition comprises: (a) about35% to about 70% by mass of one or more flowability enhancers; (b) about20% to about 50% by mass of one or more release modifiers; and (c) about1% to about 30% by mass of one or more active pharmaceuticalingredients. In one aspect, the composition further comprises: (d) about0.05% to about 0.5% of one or more antioxidants. In another aspect, thecomposition comprises: (a) glyceryl monolinoleate; (b) polyethyleneoxide; and (c) oxycodone hydrochloride. In another aspect, thecomposition further comprises: (d) butylated hydroxytoluene (BHT); and(e) butylated hydroxyanisole (BHA). In another aspect, the compositioncomprises: (a) about 50% to about 70% by mass of glyceryl monolinoleate;(b) about 25% to about 40% by mass of polyethylene oxide; and (c) about1% to about 20% by mass of oxycodone hydrochloride. In another aspect,the composition further comprises: (d) about 0.05% to about 0.4% by massof BHA; and (e) about 0.05% to about 0.2% by mass of BHT. In anotheraspect, the composition comprises: (a) about 55% to about 65% by mass ofglyceryl monolinoleate; (b) about 30% to about 35% by mass ofpolyethylene oxide; and (c) about 1% to about 15% by mass of oxycodonehydrochloride. In another aspect, the composition further comprises: (d)about 0.1% to about 0.4% by mass of BHA; and (e) about 0.05% to about0.1% by mass of BHT. In another aspect, the composition comprises:

(a) about 50% to about 70% by mass of glyceryl monolinoleate; (b) about25% to about 40% by mass of polyethylene oxide; (c) about 0.1% to about0.4% by mass of BHA; (d) about 0.05% to about 0.1% by mass of BHT; and(e) about 1% to about 20% of by mass of oxycodone hydrochloride.

Another embodiment described herein is an oral abuse deterrentpharmaceutical composition comprising: (a) about 50% to about 70% bymass glyceryl monolinoleate; (b) about 25% to about 40% by masspolyethylene oxide comprising a molecular weight of about 4,000,000; and(c) about 1% to about 20% by mass of oxycodone hydrochloride; andwherein the composition forms an abuse deterrent elastic semi-solidcomposition after being heated at a temperature of about 50° C. to about80° C. for a time period of about 10 min to about 180 min and thencooling the composition to room temperature. In one aspect, the activepharmaceutical ingredient comprises about 5 mg, about 10 mg, about 15mg, about 20 mg, about 30 mg, or about 40 mg of oxycodone hydrochloride.In another aspect, the composition is encapsulated in a capsule. Inanother aspect, the composition is encapsulated in a soft capsule. Inanother aspect, the soft capsule comprises one or more film formingpolymers, one or more plasticizers, one or more solvents, andoptionally: one or more opacifying agents, one or more coloring agents,one or more pharmaceutical excipients, or combination thereof. Inanother aspect, the soft capsule comprises: (a) about 25% to about 50%of one or more film-forming polymers; (b) about 15% to about 25% of oneor more plasticizers; (c) about 20% to about 40% of one or moresolvents; and (d) optionally, one or more opacifying agents, one or morecoloring agents, one or more pharmaceutical excipients, or combinationthereof. In another aspect, the soft capsule comprises gelatin,glycerol, water, and optionally, titanium oxide, and/or a coloringagent. In another aspect, the soft capsule is coated with one or morecoatings. In another aspect, the coating comprises polyvinyl alcohol. Inanother aspect, the coating comprises about 5% to about 15% of weightgain to the dosage form. In another aspect, the coating thickness isabout 150 μm to about 200 μm.

Another embodiment described herein is a method for manufacturing atamper resistant, abuse deterrent dosage form comprising: (a) combiningone or more flowability enhancers, one or more viscosity modifiers, andone or more active pharmaceutical ingredients; (b) encapsulating thecomposition into capsules; (c) incubating the capsules at an elevatedtemperature for a period of time; and (d) cooling the capsules to roomtemperature. In one aspect, the capsules produced in step (b) are coatedwith a coating prior to the annealing of step (c). In another aspect,the capsules are incubated in step (c) at about 50° C. to about 80° C.for about 10 min to about 180 min. In another aspect, the capsules arecooled in step (d) by reducing the temperature at a rate of about 2° C.to about 10° C. per about 5 to about 15 min (e.g., a decrease of about5° C. every 10 min).

Another embodiment described herein is an oral tamper resistant dosageform produced by any of the methods described herein comprisingoxycodone hydrochloride.

Another embodiment described herein is a n oral abuse deterrentcontrolled release dosage form comprising a capsule encapsulating: (a)about 50% to about 70% by mass glyceryl monolinoleate; (b) about 25% toabout 40% by mass polyethylene oxide comprising a molecular weight ofabout 4,000,000; and (c) about 1% to about 20% by mass of oxycodonehydrochloride; and the dosage form having been heated to about 50° C. toabout 80° C. for about 10 min to about 180 min, and cooled to roomtemperature by reducing the temperature at a rate of about 2° C. toabout 10° C. per about 5 to about 15 min. In another aspect, the dosageform exhibits an in vitro dissolution rate at pH 1.2 of about 50% afterabout 90 min. In another aspect, the pharmaceutical dosage form exhibitsan in vitro dissolution rate in water under boiling conditions of lessthan about 35% to about 60% after about 10 minutes to about 45 minutes.In another aspect, the pharmaceutical composition exhibits an in vitrodissolution rate in an aqueous alcohol solution or distilled water ofless than about 20% to about 50% after about 30 minutes to about 360minutes.

Another embodiment described herein is a method for treating, reducingthe symptoms of, or retarding the onset of pain comprising administeringto a subject in need thereof of an oral pharmaceutical compositioncomprising glyceryl monolinoleate, polyethylene oxide, and oxycodone. Inone aspect, in the pharmaceutical composition comprises: (a) about 50%to about 70% by mass glyceryl monolinoleate; (b) about 25% to about 40%by mass polyethylene oxide; and (c) about 1% to about 20% by mass ofoxycodone hydrochloride. In another aspect, the pain arises from one ormore of diabetic neuropathy, chronic arthritis, osteoarthritis,rheumatoid arthritis, acute tendonitis, bursitis, headaches, migraines,chronic neuropathies, shingles, premenstrual symptoms, sports injuries,malignancy, radiculopathy, sciatica/sciatic pain, sarcoidosis,necrobiosis, lipoidica, granuloma annulare, trauma, cancer, or acombination thereof.

Another embodiment described herein is a method for delivering about 10mg to about 120 mg of oxycodone comprising administering to a subjectone or more doses of a pharmaceutical composition comprising glycerylmonolinoleate, polyethylene oxide, and oxycodone, the method capable ofachieving one or more of the following pharmacokinetic parameters: (a) amean plasma oxycodone T_(max) of about 1 hours to about 8 hours; (b) amean plasma oxycodone C_(max) of about 10 ng/mL to about 150 ng/mL; or(c) a mean plasma oxycodone AUC_(0→∞) of about 100 h·ng/mL to about 1000h·ng/mL.

Another embodiment described herein is a method for delivering about 40mg of oxycodone comprising administering to a subject one or more dosageforms comprising glyceryl monolinoleate, polyethylene oxide, andoxycodone, the method capable of achieving one or more of the followingpharmacokinetic parameters: (a) a mean plasma oxycodone T_(max) of about4.5 hours to about 5.0 hours; (b) a mean plasma oxycodone C_(max) ofabout 40 ng/mL to about 65 ng/mL; (c) a mean plasma oxycodone AUC_(0→τ)of about 400 h·ng/mL to about 500 h·ng/mL; (d) a mean plasma oxycodoneAUC_(0→∞) of about 400·h·ng/mL to about 500 h·ng/mL; (e) a meanoxycodone half-life (t_(1/2)) of about 4.4 hours to about 4.6 hours; or(f) a mean oxycodone overall elimination rate constant (λ_(z)) of about0.14 h⁻¹ to about 0.17 h⁻¹. In one aspect, the pharmaceutical dosageform exhibits an in vitro dissolution rate at pH 1.2 of about 50% afterabout 90 minutes.

Another embodiment described herein is a method for inhibitingextraction of oxycodone from a pharmaceutical composition, the methodcomprising: providing a dosage form as described herein, wherein thedosage form is resistant to crushing, grating, grinding, cutting,solvation, or dissolution in water or alcohol. In one aspect, thepharmaceutical composition comprises a coated soft capsule.

Another embodiment described herein is an oral abuse deterrentcontrolled release pharmaceutical composition comprising glycerylmonolinoleate, polyethylene oxide, and oxycodone, the composition havingbeen heated to about 50° C. to about 80° C. for about 10 min to about180 min, and cooled to room temperature, wherein the abuse deterrentcontrolled release pharmaceutical composition comprises a means forinhibiting the crushing, grating, grinding, cutting, solvating, ordissolving of the composition.

Another embodiment described herein is a kit for dispensing an abusedeterrent dosage form comprising: (a) one or more dosage forms asdescribed herein; (b) one or more receptacles comprising a tamperevident, moisture proof packaging that reduces the ability of removingthe dosage form comprising blister or strip packs, aluminum blister,transparent or opaque polymer blister with pouch, polypropylene tubes,colored blister materials, tubes, bottles, and bottles optionallycontaining a child-resistant feature, optionally comprising a desiccant,such as a molecular sieve or silica gel; and (c) optionally, an insertcomprising instructions or prescribing information for the dosage form.

One embodiment described herein is an oral pharmaceutical compositioncomprising: (a) glyceryl monolinoleate; (b) polyethylene oxide; and (c)oxycodone or a salt thereof. In one aspect, the composition forms anabuse deterrent elastic semi-solid composition after being heated at atemperature of about 50° C. to about 80° C. for a time period of about10 min to about 180 min and then cooling the composition to roomtemperature. In another aspect, a ratio of polyethylene oxide toglyceryl monolinoleate is about 1:2. In another aspect, a ratio ofoxycodone to polyethylene oxide comprises a range of about 1:1 to about1:15. In another aspect, the glyceryl monolinoleate comprises about 35%to about 70% of the composition by mass. In another aspect, thepolyethylene oxide comprises about 20% to about 50% of the compositionby mass. In another aspect, the oxycodone comprises about 1% to about30% of the composition by mass. In another aspect, the compositionfurther comprises one or more antioxidants. In another aspect, theantioxidant comprises about 0.05% to about 0.5% of the composition bymass. In another aspect, the antioxidant comprises butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), or a combinationthereof. In another aspect, the polyethylene oxide comprises apolyethylene oxide having a molecular weight (M_(v)) of about 1,00,000to about 7,000,000. In another aspect, the polyethylene oxide comprisesa polyethylene oxide having an average molecular weight (M_(v)) of about4,000,000. In another aspect, the oxycodone comprises oxycodonehydrochloride or oxycodone myristate. In another aspect, the oxycodonecomprises about 5 mg to about 120 mg of oxycodone hydrochloride. Inanother aspect, the oxycodone comprises about 5 mg, about 10 mg, about15 mg, about 20 mg, about 30 mg, or about 40 mg of oxycodonehydrochloride.

In another embodiment, the composition comprises: (a) about 35% to about70% by mass of glyceryl monolinoleate; (b) about 20% to about 50% bymass of polyethylene oxide; and (c) about 1% to about 30% by mass ofoxycodone hydrochloride. In one aspect, the composition furthercomprises: (d) about 0.1% to about 0.4% by mass of BHA; and (e) about0.05% to about 0.1% by mass of BHT. In another aspect, the compositioncomprises: (a) about 50% to about 70% by mass of glyceryl monolinoleate;(b) about 25% to about 40% by mass of polyethylene oxide; (c) about 0.1%to about 0.4% by mass of BHA; (d) about 0.05% to about 0.1% by mass ofBHT; and (e) about 1% to about 20% of by mass of oxycodonehydrochloride.

Another embodiment described herein is an oral abuse deterrentcontrolled release dosage form comprising a capsule encapsulating: (a)about 50% to about 70% by mass glyceryl monolinoleate; (b) about 25% toabout 40% by mass polyethylene oxide comprising an average molecularweight (M_(v)) of about 4,000,000; and (c) about 1% to about 20% by massof oxycodone hydrochloride; and the dosage form having been heated toabout 50° C. to about 80° C. for about 10 min to about 180 min, andcooled to room temperature by reducing the temperature at a rate ofabout 2° C. to about 10° C. over about 5 to about 15 min (e.g., adecrease of about 5° C. every 10 min). In one aspect, the oxycodonehydrochloride comprises about 5 mg, about 10 mg, about 15 mg, about 20mg, about 30 mg, or about 40 mg of oxycodone hydrochloride. In anotheraspect, the capsule is coated with a polyvinyl alcohol coating. Inanother aspect, the dosage form exhibits an in vitro dissolution rate atpH 1.2 of about 50% after about 90 minutes. A method for treating,reducing the symptoms of, or retarding onset of pain comprisingadministering to a subject in need thereof a dosage form as describedherein.

Another embodiment described herein is a method for inhibitingextraction of oxycodone from a pharmaceutical composition, the methodcomprising: providing a dosage form as described herein, wherein thedosage form is resistant to crushing, grating, grinding, cutting,solvation, or dissolution in water or alcohol.

Another embodiment described herein is a kit for dispensing an abusedeterrent dosage form comprising: (a) one or more dosage forms asdescribed herein; (b) one or more receptacles comprising a tamperevident, moisture proof packaging that reduces the ability of removingthe dosage form comprising blister or strip packs, aluminum blister,transparent or opaque polymer blister with pouch, polypropylene tubes,colored blister materials, tubes, bottles, and bottles optionallycontaining a child-resistant feature, optionally comprising a desiccant,such as a molecular sieve or silica gel; and (c) optionally, an insertcomprising instructions or prescribing information for the dosage form.

Another embodiment described herein is a method for manufacturing anabuse deterrent dosage form comprising: (a) combining glycerylmonolinoleate, polyethylene oxide, and oxycodone; (b) encapsulating thecombination into capsules; (c) incubating the capsules at an elevatedtemperature for a period of time; and (d) cooling the capsules to roomtemperature. In one aspect, the capsules produced in step (b) are coatedwith a coating prior to the incubating of step (c). In another aspect,the capsules are incubated in step (c) at about 50° C. to about 80° C.for about 10 min to about 180 min. In another aspect, the capsules arecooled in step (d) by reducing the temperature at a rate of about 2° C.to about 10° C. over about 5 to about 15 min (e.g., a decrease of about5° C. every 10 min).

Another embodiment described herein is a method for treating paincomprising administering to a subject a pharmaceutical dosage formcomprising glyceryl monolinoleate, polyethylene oxide, and about 40 mgoxycodone, the method capable of achieving one or more of the followingpharmacokinetic parameters: (a) a mean plasma oxycodone T_(max) of about4.5 hours to about 5.0 hours; (b) a mean plasma oxycodone C_(max) ofabout 40 ng/mL to about 65 ng/mL; (c) a mean plasma oxycodone AUC_(0→τ)of about 400 h·ng/mL to about 500 h·ng/mL; (d) a mean plasma oxycodoneAUC_(0→∞) 0 of about 400·h·ng/mL to about 500 h·ng/mL; (e) a meanoxycodone half-life (t_(1/2)) of about 4.4 hours to about 4.6 hours; or(f) a mean oxycodone overall elimination rate constant (λ_(z)) of about0.14 h⁻¹ to about 0.17 h⁻¹. In one aspect, the pharmaceutical dosageform exhibits an in vitro dissolution rate at pH 1.2 of about 50% afterabout 90 minutes.

Another embodiment described herein is an abuse deterrent oralpharmaceutical composition comprising a tamper resistant controlledrelease composition comprising: (a) one or more flowability enhancers;(b) one or more release modifiers; and (c) one or more activepharmaceutical ingredients; wherein the matrix is resistant totampering. In one aspect described herein, the tamper resistantcontrolled release matrix further comprises at least one antioxidant. Inanother aspect described herein, the tamper resistant controlled releasematrix further comprises at least one or more viscosity modifiers. Inanother aspect described herein, the one or more flowability enhancerscomprise about 35% to about 70% of the total matrix mass. In anotheraspect described herein, the at least one or more release modifierscomprise from about 20% to about 50% of the total matrix mass. Inanother aspect described herein, the at least one active pharmaceuticalingredient comprise about 0.1% to about 35% of the total matrix mass. Inanother aspect described herein, the at least one antioxidant comprisesabout 0.05% to about 0.5% of the total matrix mass. In another aspectdescribed herein, the at least one or more viscosity modifiers compriseabout 0.5% to about 8% of the total matrix mass. In another aspectdescribed herein, the ratio of the active pharmaceutical ingredientpercent mass to the matrix percent mass is about 1:1000 to about 1:3. Inanother aspect described herein, the one or more flowability enhancerscomprises a non-ionic surfactant, an anionic surfactant, a zwitterionicsurfactant, or a cationic surfactant or a combination thereof. Inanother aspect described herein, the one or more flowability enhancerscomprises a non-ionic surfactant. In another aspect described herein,the one or more flowability enhancers have a hydrophilic lipophilicbalance of less than about 5. In another aspect described herein, theone or more flowability enhancers comprise a medium chain mono-, di-, ortri-glyceride; or a liquid lipophilic vehicle. In another aspectdescribed herein, the one or more flowability enhancers compriseglyceryl monocaprylate, glyceryl monocaprylcaprate, glycerylmonolinoleate, or oleic acid. In another aspect described herein, theone or more release modifiers comprise a high molecular weightpolyethylene oxide. In another aspect described herein, the one or morerelease modifiers comprises a polyethylene oxide having, a carboxyvinylpolymer or a mixture thereof. In another aspect, the molecular weight ofthe polyethylene oxide is about 5,000,000; about 6,000,000, about7,000,000, about 8,000,000, about 9,000,000, or about 10,000,000. Inanother aspect described herein, the one or more viscosity modifierscomprises polyvinyl pyrrolidone or ethylcellulose, or a mixture thereof.In another aspect described herein, the antioxidant comprisesalpha-tocopherol, beta-tocopherol, gamma-tocopherol, delta-tocopherol,butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), citricacid, ascorbic acid, carnosic acid, carnosol, rosmanol, epirosmanol,isorosmanol, methyl carnosate, rosmarinic acid, eugenol, eugenylacetate, clove bud extract, methanolic extract, epigallocatechingallate, epicatechin gallate, epigallocatechin, epicatechin, or acombination thereof. In another aspect described herein, the tamperresistant controlled release matrix forms a semi-solid elasticcomposition after being heated at a temperature of about 50° C. to about90° C. for a period of time of about 0.1 hours to about 3 hours. Inanother aspect described herein, the active pharmaceutical ingredientcomprises at least one of: hydrocodone, morphine, morphine analogues, ormorphine antagonists, tapentadol, codeine, morphine, methadone, fentanyland analogs, hydrocodone hydrochloride, hydrocodone bitartrate,hydromorphone, oxymorphone, oxycodone, meperidine, propoxyphene,flunitrazepam, barbiturates, amytal, nembutal, seconal, phenobarbital;benzodiazepines, zolpidem, zaleplon, eszopiclone, amphetamines,methylphenidate, or a combination thereof. In another aspect describedherein, the active pharmaceutical ingredient comprises oxycodone or anypharmaceutically acceptable salt thereof.

In another embodiment described herein, the active pharmaceuticalingredient comprises oxycodone and a second active pharmaceuticalingredient that reduces the symptoms of, or onset of, or prophylaxis, ofa bowel dysfunction due to acute or chronic opioid use. In anotheraspect described herein, the second active pharmaceutical ingredientcomprises a peripherally acting mu-opioid receptor antagonist comprisingmethylnaltrexone, naltrexone, naloxone, naloxegol, alvimopan or acombination thereof. In another aspect described herein, theperipherally acting mu-opioid receptor antagonist comprisesmethylnaltrexone, naltrexone, naloxone or a combination thereof. Inanother aspect described herein, the peripherally acting mu-opioidreceptor antagonist comprises naloxone. In another aspect describedherein, the active pharmaceutical ingredient comprises naloxone andoxycodone. In another aspect described herein, the at least one activepharmaceutical ingredient comprises naltrexone and oxycodone.

In another embodiment described herein, the tamper resistant controlledrelease matrix comprises: (a) glyceryl monocaprylate, oleic acid, orglyceryl monolinoleate; (b) polyethylene oxide; and (c) oxycodone; andoptionally one or more of (d) a carboxyvinyl polymer; (e) BHT; and (f)BHA. In one aspect, the tamper resistant controlled release matrixfurther comprises polyvinylpyrrolidone or ethylcellulose. In anotheraspect described herein, the tamper resistant controlled release matrixcomprises: (a) about 50% to about 65% mono- and di-glycerides (e.g.,Capmul® MCM), oleic acid, or glyceryl monolinoleate; (b) about 25% toabout 35% polyethylene oxide having a molecular weight of about4,000,000 or about 7,000,000; and (c) about 2% to about 10% ofoxycodone; and optionally (d) about 1% of carboxyvinyl polymer (e.g.,Carbopol® 974P); (e) about 0.25% BHT; and (f) about 0.1% BHA. In anotheraspect, the tamper resistant controlled release matrix further comprisesabout 1% to about 5% of polyvinylpyrrolidone K90 or about 1% to about 5%ethylcellulose 20 cP (e.g., Ethocel™ 20 cP). In another aspect describedherein, the tamper resistant controlled release matrix further comprisesa peripherally acting mu-opioid receptor antagonist comprising naloxone,methyl naltrexone, or naltrexone. In another aspect described herein,the weight percentage ratio of naloxone methyl naltrexone or naltrexoneto oxycodone is about 15:1 to about 1:18. In another aspect describedherein, the weight percentage ratio of naloxone to oxycodone is about1:2.

In another embodiment described herein, the capsule shell comprises asoft capsule shell. In another embodiment described herein, the capsuleshell comprises a hard capsule shell.

In another embodiment described herein the soft capsule shell comprisesa film forming polymer, a plasticizer, a solvent, and optionally, anopacifying agent, a coloring agent, or a pharmaceutical excipient.

In one aspect described herein, the soft capsule shell comprises: (a)about 25% to about 50% of at least one film-forming polymer; (b) about15% to about 25% of at least one plasticizer; (c) about 20% to about 40%of a solvent; (d) optionally, an opacifying agent, a coloring agent, apharmaceutical excipient, or combination thereof. In another aspectdescribed herein, the soft capsule shell comprises: (a) about 42% of atleast one film-forming polymer; (b) about 20% of at least oneplasticizer; (c) about 38% of a solvent; (d) optionally, about 0.7% ofan opacifying agent; and (e) optionally, about 0.1% at least onecoloring agent. In another aspect described herein, the soft capsuleshell comprises gelatin, glycerol, water, and optionally, titaniumoxide, and a coloring agent.

Another embodiment described herein is a method of making the tamperresistant controlled release matrix dosage form as described hereincomprising the steps of (a) suspending one or more release modifiers inone or more flowability enhancers to form a first mixture and (b) addingone or more active pharmaceutical ingredients to the first mixture toform a matrix mixture that may be encapsulated in a soft capsule shellor a hard capsule shell. In one aspect, step (a) further comprisesdissolving one or more viscosity modifiers in the one or moreflowability enhancers.

Another embodiment described herein is a method for manufacturing a softcapsule shell and a tamper resistant controlled release matrixcomprising: (a) providing a matrix comprising the composition asdescribed herein made by the methods of manufacturing described herein;(b) providing a soft capsule gel mass described herein; (c) casting thesoft capsule gel mass into films using heat-controlled drums orsurfaces; (d) forming a soft capsule comprising the matrix compositionusing rotary die encapsulation technology; and (e) heating the formedcapsules for about 1 hour at about 70° C. to form an annealed softcapsule shell, wherein following heating, the matrix has tamperresistant controlled release properties.

Another embodiment described herein is a soft or hard capsule comprisinga tamper resistant controlled release matrix produced by the methodsdescribed herein.

Another embodiment described herein is an enteric soft capsulecomprising a tamper resistant controlled release matrix produced by themethod described herein.

Another embodiment described herein is a tamper resistant oralpharmaceutical composition comprising a tamper resistant controlledrelease matrix comprising: (a) about 50% to about 65% mono- anddi-glycerides (e.g., Capmul® MCM); (b) about 25% to about 35%polyethylene oxide having a molecular weight of about 4,000,000 or about7,000,000; and (c) about 2% to about 10% of oxycodone; and optionally(d) about 1% of carboxyvinyl polymer (e.g., Carbopol® 974P); (e) about0.25% BHT; and (f) about 0.1% BHA; wherein the matrix is resistant totampering and has controlled release properties; the matrix beingencapsulated in a soft capsule shell comprising: (g) about 25% to about50% gelatin; (h) about 15% to about 25% glycerol; (i) about 20% to about40% water; and (j) optionally, an opacifying agent, a coloring agent, apharmaceutical excipient, or combination thereof. In one aspectdescribed herein, the tamper resistant controlled release matrix furthercomprises a peripherally acting mu-opioid receptor antagonist comprisingnaloxone, methyl naltrexone, or naltrexone. In another aspect describedherein, the weight percentage ratio of naloxone, methyl naltrexone ornaltrexone to oxycodone is about 15:1 to about 1:18. In another aspectdescribed herein, the weight percentage ratio of naloxone to oxycodoneis about 1:2.

Another embodiment described herein is a tamper resistant oralpharmaceutical composition comprising a tamper resistant controlledrelease matrix comprising: (a) about 50% to about 65% mono- anddi-glycerides (e.g., Capmul® MCM); (b) about 25% to about 35%polyethylene oxide having a molecular weight of about 4,000,000 or about7,000,000; and (c) about 10% of oxycodone; (g) about 1% to about 5% ofnaloxone; and optionally (d) about 1% of carboxyvinyl polymer (e.g.,Carbopol® 974P); (e) about 0.25% BHT; and (f) about 0.1% BHA; whereinthe matrix is resistant to tampering and has controlled releaseproperties; the matrix being encapsulated in a soft capsule shellcomprising: (g) about 25% to about 50% gelatin; (h) about 15% to about25% glycerol; (i) about 20% to about 40% water; and (j) optionally, anopacifying agent, a coloring agent, a pharmaceutical excipient, orcombination thereof.

Another embodiment described herein is a tamper resistant oralpharmaceutical composition comprising a tamper resistant controlledrelease matrix comprising: (a) about 50% to about 65% mono- anddi-glycerides (e.g., Capmul® MCM); (b) about 25% to about 35%polyethylene oxide having a molecular weight of about 4,000,000 or about7,000,000; (c) about 1% to about 5% polyvinylpyrrolidone K90 (d) about2% to about 10% of oxycodone; and optionally (e) about 0.25% BHT; and(f) about 0.1% BHA; wherein the matrix is resistant to tampering and hascontrolled release properties; the matrix being encapsulated in a softcapsule shell comprising: (g) about 25% to about 50% gelatin; (h) about15% to about 25% glycerol; (i) about 20% to about 40% water; and (j)optionally, an opacifying agent, a coloring agent, a pharmaceuticalexcipient, or combination thereof.

Another embodiment described herein is a tamper resistant oralpharmaceutical composition comprising a tamper resistant controlledrelease matrix comprising: (a) about 50% to about 65% oleic acid; (b)about 25% to about 35% polyethylene oxide having a molecular weight ofabout 4,000,000 or about 7,000,000; (c) about 1% to about 5%ethylcellulose 20 cP (e.g., Ethocel™ 20 cP); (d) about 2% to about 10%of oxycodone; and optionally (e) about 0.25% BHT; and (f) about 0.1%BHA; wherein the matrix is resistant to tampering and has controlledrelease properties; the matrix being encapsulated in a soft capsuleshell comprising: (g) about 25% to about 50% gelatin; (h) about 15% toabout 25% glycerol; (i) about 20% to about 40% water; and (j)optionally, an opacifying agent, a coloring agent, a pharmaceuticalexcipient, or combination thereof.

Another embodiment described herein is a tamper resistant oralpharmaceutical composition comprising a tamper resistant controlledrelease matrix comprising: (a) about 50% to about 65% glycerylmonolinoleate (e.g., Maisine™ 35-1); (b) about 25% to about 35%polyethylene oxide having a molecular weight of about 4,000,000 or about7,000,000; and (c) about 2% to about 10% of oxycodone; and optionally(e) about 0.25% BHT; and (f) about 0.1% BHA; wherein the matrix isresistant to tampering and has controlled release properties; the matrixbeing encapsulated in a soft capsule shell comprising: (g) about 25% toabout 50% gelatin; (h) about 15% to about 25% glycerol; (i) about 20% toabout 40% water; and (j) optionally, an opacifying agent, a coloringagent, a pharmaceutical excipient, or combination thereof.

Another embodiment described herein is a method for treating, reducingthe symptoms or onset of, or prophylaxis of pain stemming from diabeticneuropathy, chronic arthritis, osteoarthritis, rheumatoid arthritis,acute tendonitis, bursitis, headaches, migraines, chronic neuropathies,shingles, premenstrual symptoms, sports injuries, malignancy,radiculopathy, sciatica/sciatic pain, sarcoidosis, necrobiosis,lipoidica or granuloma annulare comprising administering to a subject inneed thereof the pharmaceutical composition as described herein. In oneaspect described herein, the administration is sufficient to achieve areduction of pain relative to baseline in the subject withoutsubstantially inducing one or more of opioid induced bowel disfunction(OIBD) comprising constipation (opioid induced constipation; OIC),anorexia, nausea and vomiting, gastro-oesophageal reflux, delayeddigestion, abdominal pain, flatulence, bloating, hard stools, incompleteevacuation or straining during bowel movements.

Another embodiment described herein is a method for delivering about a10 mg to about 80 mg dose of oxycodone comprising administering to asubject a pharmaceutical composition comprising oxycodone and otherpharmaceutically acceptable excipients in a tamper resistant matrix in asoft gel capsule, the method capable of achieving one or more of thefollowing pharmacokinetic parameters: (a) a mean plasma oxycodoneT_(max) of about 1 hours to about 8 hours; (b) a mean plasma oxycodoneC_(max) of about 10 ng/mL to about 150 ng/mL; (c) a mean plasmaoxycodone AUC_(0→∞) of about 100 h·mg/L to about 1000 h·mg/L.

In one aspect described herein, the method further comprises deliveringa dose of a peripherally acting mu-opioid receptor antagonist comprisingnaloxone, methyl naltrexone, or naltrexone. In another aspect describedherein, the weight percentage ratio of naloxone methyl naltrexone ornaltrexone to oxycodone is about 15:1 to about 1:18. In another aspectdescribed herein, the weight percentage ratio of naloxone to oxycodoneis about 1:2.

In another aspect described herein, the administration of thecompositions described herein is sufficient to achieve a reduction ofpain relative to baseline in the subject without substantially inducingone or more of opioid induced bowel disfunction (OIBD) comprisingconstipation (opioid induced constipation), anorexia, nausea andvomiting, gastro-oesophageal reflux, delayed digestion, abdominal pain,flatulence, bloating, hard stools, incomplete evacuation, or strainingduring bowel movements.

In another aspect described herein, the administration of thecompositions described herein provides an improvement of bowel functionduring pain therapy, comprising an improvement of the mean bowelfunction score of at least about 5, at least about 8, at least about 10,or at least about 15 after steady state administration to humanpatients, wherein the mean bowel function score is measured with anumerical analog scale ranging from 0 to 100. In another aspectdescribed herein, the pharmaceutical composition comprises the tamperresistant controlled release matrix as described herein.

In another aspect described herein, the pharmaceutical compositionexhibits an in vitro dissolution rate at pH 1.2, of about 35% to about95% after about 60 minutes to about 480 minutes. In another aspectdescribed herein, the pharmaceutical composition exhibits an in vitrodissolution rate at pH 1.2, of less than about 20% after about 60minutes to about 480 minutes. In another aspect described herein, thepharmaceutical composition exhibits an in vitro dissolution rate underboiling conditions of less than about 35% to about 60% after about 10minutes to about 45 minutes. In another aspect described herein, thepharmaceutical composition exhibits an in vitro dissolution rate in anaqueous alcohol solution or distilled water of less than about 20% toabout 50% after about 30 minutes to about 360 minutes.

Another embodiment described herein is method for reducing the abilityof a subject to extract an active pharmaceutical ingredient from apharmaceutical composition though crushing, grating, grinding, cutting,or solvating or dissolving the matrix comprising: providing the abusedeterrent composition as described herein, wherein the composition isresistant to crushing, grating, grinding, cutting, solvation, ordissolution. In one aspect described herein, the pharmaceuticalcomposition comprises a soft capsule shell or hard capsule shell asdescribed herein.

Another embodiment described herein is an abuse deterrent oralpharmaceutical composition comprising a tamper resistant controlledrelease matrix, wherein the tamper resistant controlled release matrixcomprises a means for preventing the crushing, grating, grinding,cutting, solvating, or dissolving of the tamper resistant controlledrelease matrix comprising one or more active pharmaceutical ingredients.

Another embodiment described herein is a kit for dispensing the abusedeterrent oral pharmaceutical composition described herein comprising:(a) at least one soft capsule comprising a tamper resistant controlledrelease matrix comprising an active pharmaceutical ingredient; (b) atleast one receptacle comprising a tamper evident, moisture proofpackaging that reduces the ability of removing the oral pharmaceuticalcomposition comprising blister or strip packs, aluminum blister,transparent or opaque polymer blister with pouch, polypropylene tubes,colored blister materials, tubes, bottles, and bottles optionallycontaining a child-resistant feature, optionally comprising a desiccant,such as a molecular sieve or silica gel; and (c) optionally, an insertcomprising instructions or prescribing information for the activepharmaceutical ingredient.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Percent release of oxycodone from an annealed test abusedeterrent pharmaceutical composition (F1) compared to the percentrelease of oxycodone from a reference abuse deterrent pharmaceuticalcomposition in fasted state simulated gastric fluid FaSSGF and fastedstate simulated intestinal fluid FaSSIF buffer.

FIG. 2. Percent release of oxycodone from annealed and non-annealed testabuse deterrent pharmaceutical compositions (F1) compared to the percentrelease of oxycodone from a reference abuse deterrent pharmaceuticalcomposition under aqueous boiling conditions.

FIG. 3. Percent release of oxycodone from annealed test abuse deterrentpharmaceutical compositions (F1 and F2) with or without a viscositymodifier compared to the percent release of oxycodone from a referenceabuse deterrent pharmaceutical composition under aqueous boilingconditions.

FIG. 4. Percent release of oxycodone from annealed test abuse deterrentpharmaceutical compositions (F2 and F3) having different molecularweight polyethylene oxide compared to the percent release of oxycodonefrom a reference abuse deterrent pharmaceutical composition underaqueous boiling conditions.

FIG. 5. Percent release of oxycodone from an annealed test abusedeterrent pharmaceutical composition (F2) in either SGF or an 80%ethanol solution.

FIG. 6. Percent release of oxycodone from annealed test abuse deterrentpharmaceutical compositions (F4-F6) in aqueous conditions at 80° C.compared to a reference oxycodone abuse deterrent composition.

FIG. 7. Percent release of oxycodone from annealed test abuse deterrentpharmaceutical compositions (F4-F6) compared to the percent release ofoxycodone from a reference abuse deterrent pharmaceutical composition inFASSGF and FASSIF buffer.

FIG. 8. Representative thermogram data demonstrating PEO melting pointdepression results in various flowability enhancers compared to anon-flowability enhancing excipient control.

FIG. 9. Percent release of oxycodone from annealed test abuse deterrentpharmaceutical compositions (F7-F9) compared in FaSSGF and FaSSIFbuffer.

FIG. 10. Representative image of (A) a reference abuse deterrentformulation after being struck with a hammer and (B) the test abusedeterrent formulation F9 shown in Table 11.

FIG. 11. Percent release of oxycodone from annealed test abuse deterrentpharmaceutical compositions (F7-F9) compared to the percent release ofoxycodone from a reference abuse deterrent pharmaceutical composition insimulated gastric fluid.

FIG. 12. Percent release of oxycodone from annealed test abuse deterrentpharmaceutical compositions (F7-F9) compared to the percent release ofoxycodone from a reference abuse deterrent pharmaceutical composition insimulated gastric fluid containing 5% ethanol.

FIG. 13. Percent release of oxycodone from annealed test abuse deterrentpharmaceutical compositions (F7-F9) compared to the percent release ofoxycodone from a reference abuse deterrent pharmaceutical composition insimulated gastric fluid containing 20% ethanol.

FIG. 14. Percent release of oxycodone from annealed test abuse deterrentpharmaceutical compositions (F7-F9) compared to the percent release ofoxycodone from a reference abuse deterrent pharmaceutical composition insimulated gastric fluid containing 40% ethanol.

FIG. 15. Percent release of oxycodone from an annealed intact test abusedeterrent pharmaceutical composition (F9) compared to the percentrelease of oxycodone from an intact reference abuse deterrentpharmaceutical composition under aqueous boiling conditions.

FIG. 16. Percent release of hydrocodone from an intact annealed testabuse deterrent pharmaceutical composition (F10) compared to the percentrelease of hydrocodone from 10 mg and 50 mg intact reference abusedeterrent pharmaceutical compositions under aqueous boiling conditions.

FIG. 17. Percent release of oxycodone from a physically manipulated(ground with a coffee grinder) annealed test abuse deterrentpharmaceutical composition (F9) compared to the percent release ofoxycodone from a physically manipulated (crushed with a mortar andpestle) reference abuse deterrent pharmaceutical composition underaqueous boiling conditions.

FIG. 18. Percent release of oxycodone from a reference abuse deterrentpharmaceutical composition intact or manipulated by crushing with amortar and pestle, grinding with a coffee grinder, or cutting underdissolution conditions in FaSSGF using Apparatus III at 30 dips perminute.

FIG. 19. Percent release of oxycodone from a test abuse deterrentpharmaceutical composition (F9) intact or manipulated by grinding with acoffee grinder or cutting under dissolution conditions in fastedsimulated gastric fluid using Apparatus III at 30 dips per minute.

FIG. 20. Percent release of hydrocodone from a test abuse deterrentpharmaceutical composition (F10) intact or manipulated by grinding witha coffee grinder under dissolution conditions in FaSSGF using ApparatusIII at 30 dips per minute.

FIG. 21. Percent release of oxycodone from a test abuse deterrentpharmaceutical composition (F9) compared to a reference abuse deterrentpharmaceutical composition manipulated by cutting under dissolutionconditions in FaSSGF using Apparatus III at 30 dips per minute.

FIG. 22. Percent release of oxycodone from a test abuse deterrentpharmaceutical composition (F9) manipulated by cutting compared to areference abuse deterrent pharmaceutical composition manipulated bycrushing with a mortar and pestle under dissolution conditions in FaSSGFusing Apparatus III at 30 dips per minute.

FIG. 23. Test for syringability of a reference abuse deterrentpharmaceutical composition manipulated by crushing with a mortar andpestle or cutting compared to a test abuse deterrent pharmaceuticalcomposition (F9) manipulated by cutting or grinding with a coffeegrinder followed by shaking agitation for 30 minutes in container having10 mL of water

FIG. 24. Test for syringability of a reference abuse deterrentpharmaceutical composition manipulated by crushing with a mortar andpestle or cutting compared to a test abuse deterrent pharmaceuticalcomposition (F9) manipulated by cutting or grinding with a coffeegrinder followed by agitation for 30 minutes in container having 10 mLof water in a water bath at 200 RPM at 90-95° C.

FIG. 25. Mean oxycodone concentration-time profiles after administrationof formulation F11 (treatment a), formulation F8 (treatment b),formulation F9 (treatment c), formulation F7 (treatment d), and thereference product (treatment e).

FIG. 26. Mean log-transformed oxycodone concentration-time profilesafter administration of formulation F11 (treatment a), formulation F8(treatment b), formulation F9 (treatment c), formulation F7 (treatmentd), and the reference product (treatment e).

FIG. 27. A. Oval and oblong oxycodone dosage forms and representativecross-sections. B. Micrograph of a dosage form cross section showing theabuse deterrent matrix, gelatin shell, and polyvinyl alcohol (PVA)coating. The PVA coating layer is about 185 μm and the gelatin shelllayer is about 650 μm, for a total encapsulation layer of about 810-840μm.

FIG. 28. Dissolution of various oxycodone dosage forms compared with acommercial reference.

FIG. 29. Mean plasma oxycodone concentrations as a function of timeafter dosing a 40 mg oxycodone formulation (Table 23) compared with acommercial reference. Panels A and B show the same data, with B having alogarithmic y-axis.

FIG. 30. Mean plasma oxycodone concentrations as a function of timeafter dosing a 40 mg oxycodone formulation (Table 23) under fasted andfed conditions. Panels A and B show the same data, with B having alogarithmic y-axis.

DETAILED DESCRIPTION

Described herein are abuse deterrent controlled release pharmaceuticalcompositions. The pharmaceutical compositions described herein provideabuse deterrent matrices and methods for preparation thereof. Alsodescribed herein are compositions and methods for manufacturing soft orhard capsules comprising abuse deterrent controlled releasepharmaceutical matrices. In some embodiments described herein, thecapsule is a soft capsule. In some embodiments described herein, thesoft capsule is a hard capsule. In some embodiments described herein,the soft capsule is an enteric soft capsule. In some embodimentsdescribed herein, the soft capsule is an enteric hard capsule.

The term “abuse deterrent,” or “tamper resistant” as used herein, refersto a pharmaceutical composition that is resistant to tampering oraccessing the active pharmaceutical ingredient for recreational drug useor drug abuse.

The phrase “recreational drug use,” as used herein, refers to thevoluntary use of an active pharmaceutical agent or drug for anon-medical purpose to induce an effect, such as pleasure, satisfaction,euphoria, dissociation, or to enhance an experience.

The term “drug abuse,” as use herein, refers to the habitual,compulsive, or recurrent use of an active pharmaceutical agent or drug,often despite negative consequences.

The term “tampering,” as used herein, refers to any kind of actual orattempted physical manipulation or interference that may result inparticle size reduction of a pharmaceutical composition. Tampering, asused herein also includes any actual or attempted dissolution orextraction of active pharmaceutical ingredients using solvents.Compositions that are resistant to physical tampering are formulated insuch a way that the composition cannot readily reduced to a form that issuitable for abuse, such as, for example, injection or snorting, becausethe tablet cannot easily be ground, grated, dissolved, extracted, andthe like at any temperature. Examples of physical tampering include, butare not limited to, crushing, grinding, grating, cutting, crisping, andother methods of particle size reduction. Dissolution tampering includesactual or attempted actions to dissolve or extract active pharmaceuticalingredients using aqueous or organic solvents such as water, ethanol,isopropanol, ethyl acetate, acetone, ether, or the like, at anytemperature including boiling. Tampering, as used herein, includes “dosedumping.”

The term “dose dumping” or “dumping” as used herein refers to the rapidrelease of the entire amount or a significant fraction of an activepharmaceutical ingredient or drug. Drug abusers often intentionallypursue dumping of a drug from the dosage form.

The terms “drug”, “active ingredient,” “active pharmaceuticalingredient,” or “active pharmaceutical agent” as used herein refer to anagent, active ingredient, compound, or substance, compositions, ormixtures thereof, that provide a pharmacological, often beneficial,effect. Reference to a specific active ingredient includes, whereappropriate, the active ingredient and any of its pharmaceuticallyacceptable salts or esters.

The term “anti-OIC agent” as used herein refers specifically to anyagent, active ingredient, compound, substance, composition, or mixturethereof, which reduces opioid induced constipation (OIC) or one or moresymptoms thereof.

The terms “dosage” or “dose” denote any form of the active ingredientformulation that contains an amount sufficient to produce a therapeuticeffect with a single administration. The dosage form used herein is fororal administration. The oral dosage forms are soft capsules, entericsoft capsules, hard capsules, or enteric hard capsules.

The term “annealed” as used herein refers to a pharmaceuticalcomposition that has been heated to an elevated temperature (e.g., 60°C. to 80° C.) for a time period (e.g., from 10 min to 120 min) and thenslowly cooled at a specific rate (e.g., 2° C. per 10 min) to form anannealed dosage form. In some aspects, pharmaceutical compositionscomprising a capsule shell encapsulating a fill composition as describedherein may be annealed at a temperature from about 50° C. to about 90°C. for about 0.1 hours to about 5 hours, including all integers withinthe specified ranges of temperature and time. In some aspects describedherein, pharmaceutical compositions comprising a soft or hard capsuleshell encapsulating a matrix fill as described herein may be annealed ata temperature of about 70° C. from about 20 min to about 90 min,including all integers within the specified range. In some aspectsdescribed herein, pharmaceutical compositions comprising a soft or hardcapsule shell encapsulating a matrix fill as described herein may beannealed at a temperature of about 70° C. for about 1 hour. In someaspects, after annealing, the dosage form is slowly cooled to roomtemperature at a cooling rate of about 2° C. to about 10° C. per about 5min to about 20 min (e.g., 2-10° C./5-20 min). In some aspects describedherein, a capsule is coated prior to the annealing step.

The term “non-annealed” refers to a pharmaceutical compositioncomprising a soft or hard capsule shell encapsulating a matrix filldescribed herein that has not been heated following encapsulation.

The terms “active pharmaceutical ingredient load” or “drug load” as usedherein refers to the quantity (mass) of the active pharmaceuticalingredient comprised in a single soft or hard capsule fill.

The term “formulation” or “composition” as used herein refers to theactive pharmaceutical ingredient or drug in combination withpharmaceutically acceptable excipients. This includes orallyadministrable formulations as well as formulations administrable byother means.

The term “titration” as used herein refers to the incremental increasein drug dosage to a level that provides the optimal therapeutic effect.

The term “controlled release” as used herein encompasses the terms“immediate release,” “modified release,” “sustained release,” “extendedrelease,” and “delayed release.”

The terms “extended release” or “sustained release” as used hereinrefers to a composition that releases an active ingredient according toa desired profile over an extended period under physiological conditionsor in an in vitro test. By “extended period” it is meant a continuousperiod of time of at least about 1 hour; about 2 hours; about 4 hours;about 6 hours; about 8 hours; about 10 hours; about 12 hours; about 14hours; about 16 hours; about 18 hours; about 20 hours about 24 hours; oreven longer; specifically, over a period of about 18 hours underphysiological conditions or in an in vitro assay.

The term “modified release” as used herein refers to a composition thatreleases an active ingredient at a slower rate than does an immediaterelease formulation under physiological conditions or in an in vitrotest.

The term “delayed” release” as used herein refers to a composition thatreleases an active ingredient after a period of time, for exampleminutes or hours, such that the active ingredient is not releasedinitially. A delayed release composition may provide, for example, therelease of a drug or active ingredient from a dosage form, after acertain period, under physiological conditions or in an in vitro test.

As used herein, the phrase “abuse deterrent controlled release” refersto a pharmaceutical composition comprising components or a formulationthat prevents liberation of the active pharmaceutical ingredient(s) fromthe composition for potential abuse or dose dumping and the compositionprovides controlled release delivery of the active pharmaceuticalingredient upon ingestion of the composition by a subject.

The term “C_(max)” as used herein refers to the maximum observed blood(plasma, serum, or whole blood) concentration or the maximum bloodconcentration calculated or estimated from a concentration to timecurve, and is expressed in units of mg/L or ng/mL, as applicable.

The term “C_(min)” as used herein refers to the minimum observed blood(plasma, serum, or whole blood) concentration or the minimum bloodconcentration calculated or estimated from a concentration to timecurve, and is expressed in units of mg/L or ng/mL, as applicable.

The term “C_(avg)” as used herein refers to the blood (plasma, serum, orwhole blood) concentration of the drug within the dosing interval, iscalculated as AUC/dosing interval, and is expressed in units of mg/L orng/mL, as applicable.

The term “T_(max)” as used herein refers to the time afteradministration at which C_(max) occurs, and is expressed in units ofhours (h) or minutes (min), as applicable.

The term “AUC_(0→τ)” as used herein refers to area under the blood(plasma, serum, or whole blood) concentration versus time curve fromtime zero to time tau (τ) over a dosing interval at steady state, wheretau is the length of the dosing interval, and is expressed in units ofh·mg/L or h·ng/mL, as applicable. For example, the term AUC_(0→12) asused herein refers to the area under the concentration versus time curvefrom 0 to 12 hours.

The term “AUC_(0→∞)” as used herein refers to the area under the blood(plasma, serum, or whole blood) concentration versus time curve fromtime 0 hours to infinity, and is expressed in units of h·mg/L orh·ng/mL, as applicable.

The term “AUC_(last)” as used herein refers to the area under the blood(plasma, serum, or whole blood) concentration versus time curve at thelast measurable concentration of the analyte, and is expressed in unitsof h·mg/L (or h·ng/mL) for at least one or more doses of thepharmaceutical compositions described herein.

The term “AUC_(overall)” as used herein refers to the combined areaunder the blood (plasma, serum, or whole blood) concentration versustime curve, and is expressed in units of h·mg/L (or h·ng/mL) for atleast one or more doses of the pharmaceutical compositions describedherein. In one aspect, the “AUC_(overall)” refers to the combined areaunder the blood concentration versus time curve for at least two dosesof the pharmaceutical compositions described herein.

The term “treating” refers to administering a therapy in an amount,manner, or mode effective to improve a condition, symptom, or parameterassociated with a disorder.

The term “prophylaxis” refers to preventing or reducing the progressionof a disorder, either to a statistically significant degree or to adegree detectable to one skilled in the art.

The term “substantially” as used herein means to a great or significantextent, but not completely.

The phrase “room temperature” as used herein refers to about 25° C. atstandard atmospheric pressure.

The term “about” as used herein refers to any values, including bothintegers and fractional components that are within a variation of up to±10% of the value modified by the term “about.”

As used herein, “a” or “an” means one or more unless otherwisespecified.

Terms such as “include,” “including,” “contain,” “containing,” “has,” or“having,” and the like, mean “comprising.”

The term “or” can be conjunctive or disjunctive.

Described herein are pharmaceutical compositions comprising abusedeterrent controlled release matrices comprising active pharmaceuticalingredients. The matrix is structured to prevent extraction of theactive pharmaceutical ingredients.

One embodiment described herein is an oral abuse deterrent controlledrelease pharmaceutical composition that releases one or more activepharmaceutical ingredients over a period of about 12 hours.

In some embodiments, the pharmaceutical composition described hereincomprises a soft or hard capsule comprising an abuse deterrentcontrolled release matrix comprising an active pharmaceuticalingredient. In one embodiment, the active pharmaceutical ingredient isan analgesic. In another embodiment, the active pharmaceuticalingredient is an opioid agonist. In another embodiment, the activepharmaceutical ingredient is an opioid analgesic.

In another embodiment, the soft or hard capsule comprising a matrix canprovide controlled release properties. Such controlled release matrixfills are described in International Patent Application Publication No.WO 2005/009409 and WO 2006/096580, U.S. Patent Application PublicationNos. US 2006/0115527 and US 2007/0053868, and U.S. Pat. Nos. 8,293,270and 8,333,989, each of which are incorporated by reference herein forsuch teachings. In one aspect, the soft or hard capsule and matrix canbe configured to provide controlled release, extended release, sustainedrelease, delayed release, or combinations thereof.

In other embodiments, the pharmaceutical composition described hereincomprises abuse deterrent properties. These abuse deterrent propertiesreduce the likelihood that the active pharmaceutical ingredient can beextracted from the composition through mechanisms, including but notlimited to crushing, grating, grinding, or cutting of the capsule toexpose the matrix thereby facilitating solvation or extraction of theactive pharmaceutical ingredient. Exemplary and non-limiting abusedeterrent matrices useful in the pharmaceutical composition describedherein may be those found in International Application No.PCT/US2015/024464; U.S. patent application Ser. No. 14/679,233; PCTInternational Application No. PCT/US2015/054443; U.S. patent applicationSer. No. 14/877,208, each of which is incorporated by reference hereinin their entirety. In addition, the abuse deterrent properties reducethe likelihood that the active pharmaceutical ingredient can beextracted from the composition by dissolving or extracting in ethanolsolutions, dissolving in solutions having pH values from about 1 toabout 12, or dissolving in household chemical compositions, includingwater, coffee, vinegar, cola, milk, ethanol, isopropanol, acetone, ethylacetate, or other common solvents. In addition, the abuse deterrentproperties further reduce the likelihood that the active pharmaceuticalingredient can be extracted by boiling in water or ethanol solutions.

In other embodiments described herein, the matrix comprises a lipid orlipophilic vehicle that provides a suspension or a solution of theactive pharmaceutical ingredient. In one aspect, a soft or hard capsulecomprising an active pharmaceutical ingredient provides controlledrelease of the active pharmaceutical ingredient.

In other embodiments described herein, the pharmaceutical compositionprovides matrix fills for the active pharmaceutical ingredient, orderivatives thereof, based on lipids or lipophilic materials. Thematrices described herein have a hydrophobic (lipophilic) surface incontact with a hydrophilic soft capsule shell to minimize any potentialshell-fill interactions, such as when soft capsules are filled withhydrophilic materials. In one embodiment described herein are methodsfor manufacturing matrix fills comprising an abuse deterrent controlledrelease matrix comprising an active pharmaceutical ingredient in a softcapsule in the form of a suspension, where part or all of the activepharmaceutical ingredient is suspended within the matrix. In oneembodiment described herein is a soft capsule having a shell and anabuse deterrent controlled release matrix fill, wherein the matrixincludes an active pharmaceutical ingredient suspended as particleswithin the matrix.

In one embodiment described herein, an exemplary abuse deterrentcontrolled release matrix has the composition of Table 1, including allpossible iterations of the specified ranges that provide 100% for thetotal weight percentage, including or excluding optional excipients.

TABLE 1 Exemplary Abuse Deterrent Controlled Release Matrix CompositionComposition Component Exemplary Components Range (%) Flowability Mono-,di-, tri-glycerides, glyceryl 35-70 Enhancer monocaprylate; oleic acid;glyceryl monolinoleate (e.g., Maisine ™ 35-1) Release Polyethylene oxide(PEO) 20-50 Modifier (e.g., POLYOX ™) Release Carboxyvinyl polymers 0-10 Modifier 2 (e.g., Carbopol ® polymers) ViscosityPolyvinylpyrrolidone; ethylcellulose  0-10 Modifier Antioxidant BHT, BHA  0-0.5 Active Oxycodone, hydrocodone, tapentadol 0.1-50  pharmaceuticalingredient(s)

In one embodiment, the matrix may comprise one or more flowabilityenhancers. In one aspect, suitable flowability enhancers have surfactantlike properties. Exemplary and non-limiting flowability enhancers maycomprise partial triglyceride medium chain, monoglycerides, diglyceridesand triglycerides, polyethylene glycol (molecular weight of about 200 orgreater), medium chain triglycerides of caprylic/capric acid, glycerylmonooleate, glyceryl monostearate, glyceryl monolinoleate (e.g.,Maisine™ 35-1), polyglyceryl-3-dioleate, oleoyl macrogol-6 glycerides,linoleoyl macrogol-6 glycerides. In one aspect, the flowability enhancercomprises a medium chain mono- and di-glycerides (e.g., glycerylmonocaprylate or Capmul® MCM) In one aspect, the flowability enhancercomprises oleic acid. In another aspect, the flowability enhancercomprises oleic acid. In another aspect, the flowability enhancercomprises glyceryl monolinoleate (e.g., Maisine™ 35-1).

In another embodiment, the matrix may comprise one or more surfactantsas described herein. In one aspect, the flowability enhancer comprises anon-ionic surfactant, an anionic surfactant, a zwitterionic surfactant,or a cationic surfactant or a combination thereof. In another aspect,the flowability enhancer comprises a non-ionic surfactant. Exemplary andnon-limiting surfactants that may be useful in the abuse deterrentmatrices described herein comprise Suitable surfactants include:Pluronic® 10R5, Pluronic® 17R2, Pluronic® 17R4, Pluronic® 25R2,Pluronic® 25R4, Pluronic® 31R1, Pluronic® F 108, Pluronic® F 108 NF,Pluronic® F 108, Pluronic® F 108NF, Poloxamer 338, Pluronic® F 127,Pluronic® F 127 NF, Pluronic® F 127 NF 500 BHT Prill, Pluronic® F 127 NFPrill, Poloxamer 407, Pluronic® F 38, Pluronic® F 38 Pastille, Pluronic®F 68, Pluronic® F 68 LF Pastille, Pluronic® F 68 NF, Pluronic® F 68 NFPrill, Poloxamer 188, Pluronic® F68 Pastille, Pluronic® F 77, Pluronic®F 77 Micropastille, Pluronic® F 87, Pluronic® F 87 NF, Pluronic® F 87 NFPrill, Poloxamer 237, Pluronic® F 88, Pluronic® F 88 Pastille, Pluronic®F 98, Pluronic® L 10, Pluronic® L 101, Pluronic® L 121, Pluronic® L 31,Pluronic® L 35, Pluronic® L 43, Pluronic® L 61, Pluronic® L 62,Pluronic® L 62 LF, Pluronic® L 62D, Pluronic® L 64, Pluronic® L 81,Pluronic® L 92, Pluronic® N 3, Pluronic® P 103, Pluronic® P 104,Pluronic® P 105, Pluronic® P 123 Surfactant, Pluronic® P 65, Pluronic® P84, Pluronic® P 85, Adogen® 464, Alkanol® 6112, Brij® 52, Brij® 93,Brij® S2, Brij® S, Brij® 58, Brij® C10, Brij® L4, Brij® O10, Brij® O10,BRIJ® O20, Brij® S10, Brij® S20, ethylenediaminetetrakis(ethoxylate-block-propoxylate) tetrol, ethylenediaminetetrakis(ethoxylate-block-propoxylate) tetrol, ethylenediaminetetrakis(propoxylate-block-ethoxylate) tetrol, IGEPAL® CA-210, IGEPAL®CA-520, IGEPAL® CA-720, IGEPAL® CO-520, IGEPAL® CO-630, IGEPAL® CO-720,IGEPAL® CO-890, IGEPAL® DM-970, MERPOL® DA, MERPOL® HCS, MERPOL® OJ,MERPOL® SE, MERPOL® SH, MERPOL® A, Poly(ethylene glycol) sorbitantetraoleate, poly(ethylene glycol) sorbitol hexaoleate, poly(ethyleneglycol) (12), poly(ethylene glycol) (18),polyethylene-block-poly(ethylene glycol), sorbitan monopalmitate, sodiumlauryl sulfate, 2,4,7,9-tetramethyl-5-decyne-4,7-diol ethoxylate,Nonidet™ P-40, Triton™ N-101, Span® 80, Triton™ X-100, Triton™ X-114,Triton™ X-405, TWEEN® 20, TWEEN® 40, TWEEN® 60, TWEEN® 85, Zonyl®FS-300, or Zonyl® FSN.

Additional exemplary and non-limiting flowability enhancers may includehigher aliphatic alcohols; higher aliphatic acids; long chain fattyacids; saturated or unsaturated fatty acids; hydrogenated fatty acids;fatty acid glycerides; polyoxyethylated oleic glycerides; monoglyceridesand diglycerides; mono-, bi- or tri-substituted glycerides; glycerol;glyceryl palmitostearate; glyceryl behenate; diethyleneglycolpalmitostearate; polyethyleneglycol stearate; polyoxyethyleneglycolpalmitostearate; glyceryl mono palmitostearate; cetyl palmitate;polyethyleneglycol palmitostearate; dimethylpolysiloxane; mono- ordi-glyceryl behenate; fatty alcohols associated with polyethoxylatefatty alcohols; cetyl alcohol; octyl dodecanol; myristyl alcohol;isopropyl myristate, isopropyl palmitate, stearic acid, stearyl alcohol,and others known in the art.

In another embodiment, the flowability enhancer has a hydrophiliclipophilic balance (HLB) ranging from about 0 to about 20. In oneaspect, the flowability enhancer has an HLB value of less than 10. Inanother aspect, the flowability enhancer has an HLB value of between 1and 6. In another aspect, the flowability enhancer has an HLB value ofless than 5. The HLB characteristic of surfactants and other compoundscan be determined in accordance with “Physical Pharmacy: PhysicalChemical Principles in the Pharmaceutical Sciences,” Fourth Edition, pp.371-373, A. Martin, Ed., Lippincott Williams & Wilkins, Philadelphia(1993).

In another embodiment, the matrix may further include a lipid orlipophilic vehicles, such as olive oil, soybean oil, sunflower oil,canola oil, palmitoleic acid, oleic acid, myristoleic acid, linoleicacid, arachidonic acid, vegetable oil, corn oil, sun flower oil, coconutoil, cocoa oil, peanut oil, almond oil, cottonseed oil, persic oil,sesame oil, squalane oil, castor oil, fish oil, paraffin oil, or mineraloil.

In another embodiment, the matrix may comprise one or more releasemodifiers. In one aspect, the release modifier comprises a highmolecular weight polyethylene oxide or a carboxyvinyl polymer, or acombination thereof. As described herein, high molecular weightpolyethylene oxide polymers have an approximate molecular weight basedon viscosity or rheology (M_(v)) of at least about 600,000 to about10,000,000 or greater. In one aspect, the release modifier may comprisea high molecular weight polyethylene oxide having a molecular weight(M_(v)) of about 600,000 to about 10,000,000, including each integerwithin the specified range. In another aspect, the release modifier maycomprise a high molecular weight polyethylene oxide having a molecularweight (M_(v)) of about 5,000,000 to about 10,000,000, including eachinteger within the specified range. In another aspect, the releasemodifier may comprise a high molecular weight polyethylene oxide havinga molecular weight (M_(v)) of about 4,000,000 to about 7,000,000,including each integer within the specified range. In another aspect,the release modifier may comprise a high molecular weight polyethyleneoxide having a molecular weight (M_(v)) of about 600,000, about 700,000,about 800,000, about 900,000, about 1,000,000, about 2,000,000, about3,000,000, about 4,000,000, about 5,000,000, about 6,000,000, about7,000,000, about 8,000,000, about 9,000,000 or about 10,000,000. Inanother aspect, the release modifier may comprise a high molecularweight polyethylene oxide having a molecular weight (M_(v)) of about4,000,000. In another aspect, the release modifier may comprise a highmolecular weight polyethylene oxide having a molecular weight (M_(v)) ofabout 5,000,000. In another aspect, the release modifier may comprise ahigh molecular weight polyethylene oxide having a molecular weight(M_(v)) of about 7,000,000.

The molecular weight measurements of polyethylene oxide may beapproximated using rheological measurements using a viscometer. Forexample, polyethylene oxide is considered to have an approximatemolecular weight (M_(v)) of 600,000 when a 5% (by wt) aqueous solutionof polyethylene oxide using a Brookfield viscometer Model RVF, spindleNo. 2, at 2 rpm, at 25° C. shows a viscosity range of 30 to 50 mPa s(cP). Polyethylene oxide is considered to have an approximate molecularweight (M_(v)) of 1,000,000 when a 2% (by wt) aqueous solution ofpolyethylene oxide using a Brookfield viscometer Model RVF, spindle No.1, at 10 rpm, at 25° C. shows a viscosity range of 400 to 800 mPa s(cP). Polyethylene oxide is considered to have an approximate molecularweight (M_(v)) of 2,000,000 when a 2% (by wt) aqueous solution ofpolyethylene oxide using a Brookfield viscometer Model RVF, spindle No.3, at 10 rpm, at 25° C. shows a viscosity range of 2000 to 4000 mPa s(cP). Polyethylene oxide is considered to have an approximate molecularweight (M_(v)) of 4,000,000 when a 1% (by wt) aqueous solution ofpolyethylene oxide using a Brookfield viscometer Model RVF, spindle No.2, at 2 rpm, at 25° C. shows a viscosity range of 1650 to 5500 mPa s(cP). Polyethylene oxide is considered to have an approximate molecularweight (M_(v)) of 5,000,000 when a 1% (by wt) aqueous solution ofpolyethylene oxide using a Brookfield viscometer Model RVF, spindle No.2, at 2 rpm, at 25° C. shows a viscosity range of 5500 to 7500 mPa s(cP). Polyethylene oxide is considered to have an approximate molecularweight (M_(v)) of 7,000,000 when a 1% (by wt) aqueous solution ofpolyethylene oxide using a Brookfield viscometer Model RVF, spindle No.2, at 2 rpm, at 25° C. shows a viscosity range of 7500 to 10,000 mPa s(cP). Polyethylene oxide is considered to have an approximate molecularweight (M_(v)) of 8,000,000 when a 1% (by wt) aqueous solution ofpolyethylene oxide using a Brookfield viscometer Model RVF, spindle No.2, at 2 rpm, at 25° C. shows a viscosity range of 10,000 to 15,000 mPa s(cP). Suitable polyethylene oxide polymers with the above describedviscosity and molecular weight values that are useful for the matricesdescribed are, for example, POLYOX™ polymers, such as WSR-205, WSR-1105,WSR N-12K, WSR N-60K, WSR-301, WSR Coagulant, WSR-303, WSR 308, UCARFLOCPolymers 300, 302, 304, and 309 commercially available from Dow ChemicalCompany. In one aspect, the polyethylene oxide polymer is POLYOX™WSR-301 (M_(v)≈4,000,000) or POLYOX™ WSR-303 (M_(v)≈7,000,000) (DowChemical Co.). In one aspect, the polyethylene oxide polymer is POLYOX™WSR-301 (M_(v)≈4,000,000).

In another embodiment, the composition comprises one or more viscositymodifiers. Suitable and non-limiting viscosity modifiers that may bepresent in the matrices described herein comprise methylcellulose,ethylcellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose,hydroxyethyl cellulose, hydroxymethyl cellulose, polymethylmethacrylate,polyhydroxyethylmethacrylate, polyvinylpyrrolidone, copovidone,polyvinyl alcohol, a copolymer of polyvinylpyrrolidone and polyvinylacetate, or combinations thereof. For example, polymers commerciallyavailable as Methocel™ K100M, Methocel™ A4M, Ethocel™ Premium LV CR, K4MPremium CR, K15M Premium CR, K100 Premium CR, E4M Premium CR, E10MPremium CR, or E4M Premium (Dow Chemical Co.), CELLOSIZE™, or WALOCEL™CRT may be used in the abuse deterrent matrices described herein. Theseviscosity modifiers may comprise a viscosity of about 50 cP to about100,000 cP, including each integer within the specified range. Forexample, these additional release modifiers may comprise a viscosity ofabout 50 cP, about 100 cP, about 200 cP, about 300 cP, about 400 cP,about 500 cP, about 750 cP, about 1,000 cP, about 1,500 cP, about 2,000cP, about 2,500 cP, about 3,000 cP, about 3,500 cP, about 4,000 cP,about 4,500 cP, about 5,000 cP, about 6,000 cP, about 7,000 cP, about8,000 cP, about 9,000 cP, or about 10,000 cP, about 15,000 cP, about20,000 cP, about 30,000 cP, about 40,000 cP, about 50,000 cP, about60,000 cP, about 70,000 cP, about 80,000 cP, about 90,000 cP, about100,000 cP, greater than 100,000 cP, or even greater. In one embodiment,the matrix comprises hydroxylpropyl methylcellulose (e.g., Methocel™K100M). In another embodiment, the matrix comprises ethylcellulose(e.g., Ethocel™ 20 cP). In another embodiment, the matrix comprises apolyvinylpyrrolidone (e.g., polyvinylpyrrolidone K90).

In another embodiment, the abuse-deterrent matrix may optionallycomprise one or more antioxidants. Suitable antioxidants comprisetocopherols (e.g., alpha-tocopherol, beta-tocopherol, gamma-tocopherol,or delta-tocopherol), butylated hydroxytoluene (BHT), butylatedhydroxyanisole (BHA), citric acid, ascorbic acid, phenolic diterpenes(e.g., carnosic acid, carnosol, rosmanol, epirosmanol, isorosmanol, ormethyl carnosate), rosmarinic acid, eugenol, eugenyl acetate, clove budextract, methanolic extract, tea catechins (e.g., epigallocatechingallate, epicatechin gallate, epigallocatechin, or epicatechin), orcombinations thereof.

In one embodiment described herein, the abuse deterrent matrix maycomprise one or more flowability enhancers, one or more releasemodifiers, one or more active pharmaceutical ingredients, optionally oneor more antioxidants, optionally one or more viscosity modifiers,optionally one or more hydrophilic vehicles, and optionally one or moreother pharmaceutically acceptable excipients in a weight percentageamount of the matrix fill mass as further described herein.

In another embodiment, the one or more flowability enhancers comprisesfrom about 40% to about 80% of the matrix fill mass, including allintegers within the specified range. In one aspect, the one or moreflowability enhancers comprises from about 50% to about 80% of thematrix fill mass, including all integers within the specified range. Inanother aspect, the one or more flowability enhancers comprises fromabout 50% to about 60% of the matrix fill mass, including all integerswithin the specified range. In another aspect, the one or moreflowability enhancers comprises from about 50% to about 60% of thematrix fill mass, including all integers within the specified range. Inanother aspect, the one or more flowability enhancers comprises fromabout 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about70%, about 75%, or about 80% of the matrix fill mass.

In another embodiment, the one or more release modifiers comprises fromabout 20% to about 50% of the matrix fill mass, including all integerswithin the specified range. In one aspect, the one or more releasemodifiers comprises from about 25% to about 50% of the matrix fill mass,including all integers within the specified range. In another aspect,the one or more release modifiers comprises from about 25% to about 40%of the matrix fill mass, including all integers within the specifiedrange. In another aspect, the one or more release modifiers comprisesfrom about 25% to about 35% of the matrix fill mass, including allintegers within the specified range. In another aspect, the one or morerelease modifiers comprises about 20%, about 25%, about 30%, about 35%,about 40%, about 45%, or about 50% of the matrix fill mass.

In another embodiment, the one or more viscosity modifiers may comprisefrom about 0.5% to about 8% of the matrix fill mass, including allintegers within the specified range. In one aspect, the one or moreviscosity modifiers may comprise from about 0.5% to about 5% of thematrix fill mass, including all integers within the specified range. Inanother aspect, the one or more viscosity modifiers may comprise fromabout 0.5% to about 3% of the matrix fill mass, including all integerswithin the specified range. In another aspect, the one or more viscositymodifiers may comprise from about 0.5% to about 2% of the matrix fillmass, including all integers within the specified range. In anotheraspect, the one or more viscosity modifiers may comprise about 0.5%,about 0.75%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%,about 7%, or about 8%, of the matrix fill mass. In another aspect,matrix fill mass may not have any viscosity modifier.

In another embodiment, one or more antioxidants may comprise from about0.1% to about 0.5% of the matrix mass, including all integers within thespecified range. In one aspect, the one or more antioxidants maycomprise about 0.3%, 0.4%, or 0.5% of the matrix fill mass.

In another embodiment, the one or more hydrophilic polymers comprisesfrom about 1% to about 50% by weight of the matrix fill mass, includingall integers within the specified range. In one aspect, the one or morehydrophilic polymer s comprises from about 1% to about 30% of the matrixfill mass, including all integers within the specified range. In anotheraspect, the one or more hydrophilic polymers comprises from about 25% toabout 40% of the matrix fill mass, including all integers within thespecified range. In another aspect, the one or more hydrophilic polymerscomprises from about 25% to about 35% of the matrix fill mass, includingall integers within the specified range. In one aspect, the one or morehydrophilic polymer s comprises from about 1% to about 10% of the matrixfill mass, including all integers within the specified range. In anotheraspect, the one or more hydrophilic polymers comprises about 1%, about5%, about 10% about, 20%, about 25%, about 30%, about 35%, about 40%,about 45%, or about 50% of the matrix fill mass.

In another embodiment, the one or more active pharmaceutical ingredientcomprises from about 0.1% to about 50% of the matrix fill mass,including all integers within the specified range. In anotherembodiment, the one or more active pharmaceutical ingredient comprisesfrom about 1% to about 50% of the matrix fill mass, including allintegers within the specified range. In another embodiment, the one ormore active pharmaceutical ingredient comprises from about 1% to about25% of the matrix fill mass, including all integers within the specifiedrange. In one aspect, the active pharmaceutical ingredient comprisesabout 5% of the matrix fill mass. In one aspect, the activepharmaceutical ingredient comprises about 7% of the matrix fill mass. Inone aspect, the active pharmaceutical ingredient comprises about 10% ofthe matrix fill mass. In one aspect, the active pharmaceuticalingredient comprises about 20% of the matrix fill mass. In one aspect,the active pharmaceutical ingredient comprises about 25% of the matrixfill mass.

In another embodiment, the weight percentage ratio of release modifierto flowability enhancer ranges from about 0.2:1 to about 1:1.5,including all iterations of ratios within the specified range. In oneaspect, the weight percentage ratio of release modifier to flowabilityenhancer ranges from about 0.2:1 to about 0.75:1, including alliterations of ratios within the specified range. In one aspect, theweight percentage ratio of release modifier to flowability enhancerranges from about 0.2:1 to about 0.5:1, including all iterations ofratios within the specified range. In one aspect, the weight percentageratio of release modifier to flowability enhancer ranges from about0.2:1, about 0.3:1, about 0.4:1, about 0.5:1, about 0.6:1, about 0.7:1,about 0.9:1, about 1:1, about 1.1:1, or about 1.2:1.

In another embodiment, the weight percentage ratio of activepharmaceutical ingredient to the total matrix fill mass ranges fromabout 1:1000 to about 1:3, including all iterations of ratios within thespecified range. In another embodiment, the weight percentage ratio ofactive pharmaceutical ingredient to the total matrix fill mass rangesfrom about 1:100 to about 1:2, including all iterations of ratios withinthe specified range. In another embodiment, the weight percentage ratioof active pharmaceutical ingredient to the total matrix fill mass rangesfrom about 1:15 to about 1:2, including all iterations of ratios withinthe specified range. In one aspect, the weight percentage ratio ofactive pharmaceutical ingredient to the total matrix fill mass is about1:100. In another aspect, the weight percentage ratio of activepharmaceutical ingredient to the total matrix is about 1:10. In anotheraspect, the weight percentage ratio of active pharmaceutical ingredientto the total matrix fill mass is about 1:7.5. In another aspect, theweight percentage ratio of active pharmaceutical ingredient to the totalmatrix fill mass is about 1:5. In another aspect, the weight percentageratio of active pharmaceutical ingredient to the total matrix fill massis about 1:3. In another aspect, the weight percentage ratio of activepharmaceutical ingredient to the total matrix fill mass is about 1:2.

In one embodiment described herein, the abuse deterrent matrix maycomprise one or more flowability enhancers, one or more releasemodifiers, one or more active pharmaceutical ingredients, optionally oneor more viscosity modifiers, wherein the matrix comprises any one of thecompositions of Tables 7 and 9-10.

It was found that the addition of one or more flowability enhancers suchas mono- or di-glycerides (e.g., Capmul® MCM), oleic acid, and glycerylmonolinoleate (e.g., Maisine™ 35-1) increases the flowability of the oneor more release modifiers (e.g., high molecular weight polyethyleneoxide), and thus, provides for a flowable matrix suitable forencapsulation in the soft or hard capsule shells as described herein.For example, using a conventional hydrophilic vehicle, such aspolyethylene glycol, it was demonstrated that a carrier comprisingpolyethylene glycol had a high degree of miscibility with the highmolecular weight polyethylene oxide. The resulting mixtures ofpolyethylene oxide and polyethylene glycol became highly viscous at roomtemperature, which complicates further processing steps. Further, it wasfound that certain oils and lipophilic vehicles are not suitable as aflowability enhancer for the one or more release modifiers.

Thus, without being bound by any theory, it is believed that theflowable characteristics of the matrices described herein may be due tothe limited miscibility of the one or more release modifiers and the oneor more flowability enhancers described herein at room temperature. Forexample, it was found that mono- or di-glycerides (e.g., Capmul® MCM),oleic acid, or glyceryl monolinoleate (e.g., Maisine™ 35-1) allowsadequate matrix flowability at room temperature due to solubilization ofhigh molecular weight polyethylene oxide that allows standardencapsulation techniques to be employed. It was further found thatmatrix compositions comprising a flowability enhancer withsurfactant-like properties, such as for example, mono- or di-glycerides(e.g., Capmul® MCM), oleic acid, or glyceryl monolinoleate (e.g.,Maisine™ 35-1) and a high molecular weight polyethylene oxide had afluid-like consistency at room temperature.

It was further demonstrated that the flowability enhancer andpolyethylene oxide became more miscible after being heated to about 70°C. Surprisingly, it was discovered that these matrices having theflowability enhancers, such as mono- or di-glycerides (e.g., Capmul®MCM), oleic acid, or glyceryl monolinoleate (e.g., Maisine™ 35-1) whenheated to an elevated temperature of about 70° C. and then cooled toroom temperature, became an elastic, rubbery, semi-solid material havingan increased Young's modulus. In contrast, it was also unexpectedlydemonstrated that this solidifying effect did not occur for compositionshaving soybean oil as a flowability enhancer. Furthermore, it wassurprisingly and advantageously found that the process of heating andcooling the matrices comprising polyethylene oxide and a suitable flowability enhancer further allow for reduced levels of polyethylene oxideto be used, while exhibiting effective abuse deterrent and controlledrelease properties, which has previously been unrealized.

Without being bound by any theory, it is thought that the releasemodifier is suspended in the flowability enhancer throughout theprocessing steps. During the annealing steps, the release modifier isbelieved to become molten. The two components, therefore, becomemiscible at this point. This appears to be a synergistic effect whereinthe flowability enhancer reduces the melting point of the releasemodifier and also solubilizes the release modifier at the elevatedannealing temperature (which is lower than the typical melting point ofthe release modifier by about 20-50° C.). When cooled, the releasemodifier and flowability enhancer recrystallizes and forms an elasticsemi-solid composition enveloping the active pharmaceutical ingredient.For example, high molecular weight polyethylene oxide is asemi-crystalline polymer known to melt at about 100° C. In the presenceof a suitable flowability enhancer, such as mono- or di-glycerides(e.g., Capmul® MCM), oleic acid, or glyceryl monolinoleate (e.g.,Maisine™ 35-1), polyethylene oxide becomes solubilized at about 50 to80° C. After subsequent cooling, the polyethylene oxide and flowabilityenhancer mixture solidify to form an elastic, rubbery, semi-solidcomposition. Thus, the composition and annealing process describedherein unexpectedly resulted in the formation of an elastic semi-solidcomposition with advantageous abuse deterrent properties.

As described herein, the heated pharmaceutical compositions comprisingthe abuse deterrent matrix fills are in some embodiments annealed byheating the compositions. In some embodiments, the pharmaceuticalcompositions comprising a soft or hard capsule shell encapsulating amatrix fill as described herein may be annealed at a temperature ofabout 70° C. for about 1 hour or less. These annealed elastic semi-solidmatrices comprise advantageous abuse deterrent characteristics.

A common method for extracting abuse prone drugs is by boiling thecomposition. It was found that the abuse deterrent matrix fillsdescribed herein further provide for abuse deterrence by reducing thepercentage of released active pharmaceutical ingredient released duringboiling, suggesting that the matrices described herein maintain asemi-solid elastic material at high temperatures (e.g., in excess of90-100° C.). Without wishing to be bound by any theory, it is thoughtthat the lipophilic and solubilizing nature of the flowability enhancerin combination with high molecular weight polyethylene oxide provideabuse deterrent characteristics following an annealing step. Thesemi-solid elastic characteristics of the abuse deterrent matrix fillsdescribed herein further prevent or reduce the likelihood for theextraction of active pharmaceutical ingredients through the additionalmeans of crushing, grating, grinding, or cutting the dosage formsfurther described herein.

Another common method for extracting abuse prone drugs is throughethanol based extraction of the composition. It was found that the abusedeterrent matrices described herein further reduce the extraction of oneor more active pharmaceutical ingredients in high percentage Ethanolsolutions (e.g., 80%), while maintaining desired release rates ingastric-like environments. Thus, the presence of the components of theabuse deterrent matrix compositions described herein function to inhibitdrug release from the pharmaceutical compositions described herein usingcommon attempts of drug extraction. Thus, the matrix compositionsdescribed herein have abuse deterrent properties by preventing theliberation of the active ingredient for injection or insufflation andprevent solvation, dissolution, or extraction of the activepharmaceutical ingredient by use of aqueous or organic solutions.Furthermore, the matrix compositions also provide controlled releasedelivery of the active pharmaceutical ingredient after ingestion by asubject.

In one embodiment, the matrix contains an active pharmaceuticalingredient in a suspended form, soluble form, insoluble form, orcombinations thereof. The active pharmaceutical ingredient can bedispersed in the internal phase as a suspension form. A suspension asused herein means the API does not dissolve in one of the phases andremains as a solid.

In another embodiment, the matrix contains an active pharmaceuticalingredient useful for the treatment of pain. In one embodiment, the APIcomprises one or more opioid receptor agonists. In one embodiment, theactive pharmaceutical ingredient includes one or more of oxycodone,hydrocodone, oxymorphone, hydromorphone, morphine, codeine, methadone,fentanyl, tapentadol, tramadol, meperidine, propoxyphene, flunitrazepam,barbiturates, amytal, nembutal, seconal, phenobarbital; benzodiazepines,zolpidem, zaleplon, eszopiclone, amphetamines, methylphenidate, saltsthereof, or a combination thereof.

In another embodiment, the matrix comprises one or more activepharmaceutical ingredients (API). In one aspect, the activepharmaceutical ingredient is useful in treating pain. In one aspect, theactive pharmaceutical ingredient is oxycodone, hydrocodone, oxymorphone,hydromorphone, tapentadol, morphine, or codeine. In one aspect, theactive pharmaceutical ingredient is oxycodone or hydrocodone. In oneaspect, the active pharmaceutical ingredient is oxycodone.

Examples of specific active drug substances suitable for use in thepharmaceutical compositions provided herein include: anti-inflammatoryand antirheumatic active drug substances, such as, for example:butylpyrazolidine, phenylbutazone, mofebutazone, oxyphenbutazone,clofezone, kebuzone, acetic acid derivatives and related substances,indometacin, sulindac, tolmetin, zomepirac, diclofenac, alclofenac,bumadizone, etodolac, lonazolac, fentiazac, acemetacin, difenpiramide,oxametacin, proglumetacin, ketorolac, aceclofenac, bufexamac, oxicam,piroxicam, tenoxicam, droxicam, lornoxicam, meloxicam, methotrexate,propionic acid derivatives, ibuprofen, naproxen, ketoprofen, fenoprofen,fenbufen, benoxaprofen, suprofen, pirprofen, flurbiprofen, indoprofen,tiaprofenic acid, oxaprozin, ibuproxam, dexibuprofen, flunoxaprofen,alminoprofen, dexketoprofen, fenamates, mefenamic acid, tolfenamic acid,flufenamic acid, meclofenamic acid, coxibs, celecoxib, rofecoxib,valdecoxib, parecoxib, etoricoxib, lumiracoxib, nabumetone, niflumicacid, azapropazone, glucosamine, benzydamine, glucosaminoglycanpolysulfate, proquazone, orgotein, nimesulide, feprazone, diacerein,morniflumate, tenidap, oxaceprol, chondroitin sulfate, feprazone,dipyrocetyl, acetylsalicylic acid, quinolines, oxycinchophen, goldpreparations, sodium aurothiomalate, sodium aurotiosulfate, auranofin,aurothioglucose, aurotioprol, penicillamine, or bucillamine.

In another embodiment, suitable active pharmaceutical ingredients cancomprise analgesics, such as, for example: opioids, natural opiumalkaloids, morphine, opium, hydromorphone, nicomorphine, oxycodone,dihydrocodone, diamorphine, tapentadol, papaveretum, papaveretum,codeine, phenylpiperidine derivatives, ketobemidone, pethidine,fentanyl, diphenylpropylamine derivatives, dextromoramide, piritramide,dextropropoxyphene, bezitramide, methadone, benzomorphan derivatives,pentazocine, phenazocine, oripavine derivatives, buprenorphine,morphinan derivatives, butorphanol, nalbuphine, tilidine, tramadol,dezocine, salicylic acid and derivatives, acetylsalicylic acid,aloxiprin, choline salicylate, sodium salicylate, salicylamide,salsalate, ethenzamide, morpholine salicylate, dipyrocetyl, benorilate,diflunisal, potassium salicylate, guacetisal, carbasalate calcium,imidazole salicylate, pyrazolones, phenazone, metamizole sodium,aminophenazone, propyphenazone, nifenazone, anilides, paracetamol,phenacetin, bucetin, propacetamol, other analgesics and antipyretics,such as, for example: rimazolium, glafenine, floctafenine, viminol,nefopam, flupirtine, or ziconotide.

In another embodiment, suitable active pharmaceutical ingredients cancomprise anaesthetics, such as, for example: ethers, diethyl ether,vinyl ether, halogenated hydrocarbons, halothane, chloroform,methoxyflurane, enflurane, trichloroethylene, isoflurane, desflurane,sevoflurane, barbiturates, methohexital, hexobarbital, thiopental,narcobarbital, opioid anaesthetics, fentanyl, alfentanil, sufentanil,phenoperidine, anileridine, remifentanil, other general anaesthetics,such as, for example: droperidol, ketamine, propanidid, alfaxalone,etomidate, propofol, hydroxybutyric acid, nitrous oxide, esketamine,xenon, esters of aminobenzoic acid, metabutethamine, procaine,tetracaine, chloroprocaine, benzocaine, amides, bupivacaine, lidocaine,mepivacaine, prilocaine, butanilicaine, cinchocaine, etidocaine,articaine, ropivacaine, levobupivacaine, esters of benzoic acid,cocaine, other local anaesthetics, such as, for example: ethyl chloride,dyclonine, phenol, or capsaicin.

In another embodiment, suitable active pharmaceutical ingredients cancomprise antimigraine active drug substances, such as, for example:ergot alkaloids, dihydroergotamine, ergotamine, methysergide, lisuride,corticosteroid derivatives, flumedroxone, selective serotonin (5HT¹)agonists, sumatriptan, naratriptan, zolmitriptan, rizatriptan,almotriptan, eletriptan, frovatriptan, other antimigraine preparations,pizotifen, clonidine, iprazochrome, dimetotiazine, or oxetorone.

In another embodiment, suitable active pharmaceutical ingredients cancomprise antiepileptic active drug substances, such as, for example:barbiturates and derivatives, methylphenobarbital, phenobarbital,primidone, barbexaclone, metharbital, hydantoin derivatives, ethotoin,phenytoin, amino(diphenylhydantoin) valeric acid, mephenytoin,fosphenytoin, oxazolidine derivatives, paramethadione, trimethadione,ethadione, succinimide derivatives, ethosuximide, phensuximide,mesuximide, benzodiazepine derivatives, clonazepam, carboxamidederivatives, carbamazepine, oxcarbazepine, rufinamide, fatty acidderivatives, valproic acid, valpromide, aminobutyric acid, vigabatrin,progabide, tiagabine, other antiepileptics, such as, for example:sultiame, phenacemide, lamotrigine, felbamate, topiramate, gabapentin,pheneturide, levetiracetam, zonisamide, pregabalin, stiripentol,lacosamide, or beclamide.

In another embodiment, suitable active pharmaceutical ingredients cancomprise anticholinergic active drug substances, such as, for example:tertiary amines, trihexyphenidyl, biperiden, metixene, procyclidine,profenamine, dexetimide, phenglutarimide, mazaticol, bornaprine,tropatepine, ethers chemically close to antihistamines, etanautine,orphenadrine (chloride), ethers of tropine or tropine derivatives,benzatropine, or etybenzatropine.

In another embodiment, suitable active pharmaceutical ingredients cancomprise dopaminergic active drug substances, such as, for example: dopaand dopa derivatives, levodopa, melevodopa, etilevodopa, adamantanederivatives, amantadine, dopamine agonists, bromocriptine, pergolide,dihydroergocryptine mesylate, ropinirole, pramipexole, cabergoline,apomorphine, piribedil, rotigotine, monoamine, oxidase B inhibitors,selegiline, rasagiline, other dopaminergic agents, such as, for example:tolcapone, entacapone, or budipine.

In another embodiment, suitable active pharmaceutical ingredients cancomprise antipsychotic active drug substances, such as, for example:phenothiazines with aliphatic side-chain, chlorpromazine,levomepromazine, promazine, acepromazine, triflupromazine, cyamemazine,chlorproethazine, phenothiazines with piperazine structure, dixyrazine,fluphenazine, perphenazine, prochlorperazine, thiopropazate,trifluoperazine, acetophenazine, thioproperazine, butaperazine,perazine, phenothiazines with piperidine structure, periciazine,thioridazine, mesoridazine, pipotiazine, butyrophenone derivatives,haloperidol, trifluperidol, melperone, moperone, pipamperone,bromperidol, benperidol, droperidol, fluanisone, indole derivatives,oxypertine, molindone, sertindole, ziprasidone, thioxanthenederivatives, flupentixol, clopenthixol, chlorprothixene, tiotixene,zuclopenthixol, diphenylbutylpiperidine derivatives, fluspirilene,pimozide, penfluridol, diazepines, oxazepines, thiazepines, loxapine,clozapine, olanzapine, quetiapine, neuroleptics, tetrabenazine,benzamides, sulpiride, sultopride, tiapride, remoxipride, amisulpride,veralipride, levosulpiride, lithium, other antipsychotics, such as, forexample prothipendyl, risperidone, clotiapine, mosapramine, zotepine,aripiprazole, or paliperidone.

In another embodiment, suitable active pharmaceutical ingredients cancomprise anxiolytic active drug substances, such as, for example:benzodiazepine derivatives, diazepam, chlordiazepoxide, medazepam,oxazepam, potassium clorazepate, lorazepam, adinazolam, bromazepam,clobazam, ketazolam, prazepam, alprazolam, halazepam, pinazepam,camazepam, nordazepam, fludiazepam, ethyl loflazepate, etizolam,clotiazepam, cloxazolam, tofisopam, diphenylmethane derivatives,hydroxyzine, captodiame, carbamates, meprobamate, emylcamate,mebutamate, dibenzo-bicyclo-octadiene derivatives, benzoctamine,azaspirodecanedione derivatives, buspirone, other anxiolytics, such as,for example: mephenoxalone, gedocarnil, or etifoxine.

In another embodiment, suitable active pharmaceutical ingredients cancomprise hypnotic and sedative active drug substances, such as, forexample: barbiturates, pentobarbital, amobarbital, butobarbital,barbital, aprobarbital, secobarbital, talbutal, vinylbital, vinbarbital,cyclobarbital, heptabarbital, reposal, methohexital, hexobarbital,thiopental, ethallobarbital, allobarbital, proxibarbal, aldehydes andderivatives, chloral hydrate, chloralodol, acetylglycinamide chloralhydrate, dichloralphenazone, paraldehyde, benzodiazepine emeproniumderivatives, flurazepam, nitrazepam, flunitrazepam, estazolam,triazolam, lormetazepam, temazepam, midazolam, brotizolam, quazepam,loprazolam, doxefazepam, cinolazepam, piperidinedione derivatives,glutethimide, methyprylon, pyrithyldione, benzodiazepine related drugs,zopiclone, zolpidem, zaleplon, ramelteon, other hypnotics and sedatives,such as, for example: methaqualone, clomethiazole, bromisoval,carbromal, scopolamine, propiomazine, triclofos, ethchlorvynol,valerian, hexapropymate, bromides, apronal, valnoctamide,methylpentynol, niaprazine, melatonin, dexmedetomidine, ordipiperonylaminoethanol.

In another embodiment, suitable active pharmaceutical ingredients cancomprise antidepressant active drug substances, such as, for example:non-selective monoamine reuptake inhibitors, desipramine, imipramine,imipramine oxide, clomipramine, opipramol, trimipramine, lofepramine,dibenzepin, amitriptyline, nortriptyline, protriptyline, doxepin,iprindole, melitracen, butriptyline, dosulepin, amoxapine, dimetacrine,amineptine, maprotiline, quinupramine, selective serotonin reuptakeinhibitors, zimeldine, fluoxetine, citalopram, paroxetine, sertraline,alaproclate, fluvoxamine, etoperidone, escitalopram, monoamine oxidaseinhibitors, isocarboxazid, nialamide, phenelzine, tranylcypromine,iproniazide, iproclozide, monoamine oxidase A inhibitors, moclobemide,toloxatone, other antidepressants, such as, for example: oxitriptan,tryptophan, mianserin, nomifensine, trazodone, nefazodone, minaprine,bifemelane, viloxazine, oxaflozane, mirtazapine, medifoxamine,tianeptine, pivagabine, venlafaxine, milnacipran, reboxetine, gepirone,duloxetine, agomelatine, desvenlafaxine, centrally actingsympathomimetics, such as, for example: amfetamine, dexamfetamine, lisdexamfetamine, metamfetamine, methylphenidate, dexmethylphenidate,pemoline, fencamfamin, modafinil, fenozolone, atomoxetine, fenetylline,xanthine derivatives, caffeine, propentofylline, other psychostimulantsand nootropics, such as, for example meclofenoxate, pyritinol,piracetam, deanol, fipexide, citicoline, oxiracetam, pirisudanol,linopirdine, nizofenone, aniracetam, acetylcarnitine, idebenone,prolintane, pipradrol, pramiracetam, adrafinil, or vinpocetine.

In another embodiment, suitable active pharmaceutical ingredients cancomprise anti-dementia active drug substances, such as, for example:anticholinesterases, tacrine, donepezil, rivastigmine, galantamine,other anti-dementia drugs, memantine, or ginkgo biloba.

In another embodiment, suitable active pharmaceutical ingredients cancomprise other nervous system active drug substances, such as, forexample: parasympathomimetics, anticholinesterases, neostigmine,pyridostigmine, distigmine, ambenonium, choline esters, carbachol,bethanechol, and other parasympathomimetics, such as, for example,pilocarpine, or choline alfoscerate.

Active drug substances used in addictive disorders, such as, forexample: nicotine, bupropion, varenicline, disulfiram, calciumcarbimide, acamprosate, naltrexone, buprenorphine, methadone,levacetylmethadol, lofexidine, betahistine, cinnarizine, flunarizine,acetylleucine, gangliosides and ganglioside derivatives, tirilazad,riluzole, xaliproden, hydroxybutyric acid, or amifampridine.

In another embodiment, suitable active pharmaceutical ingredients cancomprise opium alkaloids and derivatives, such as, for example:ethylmorphine, hydrocodone, codeine, opium alkaloids with morphine,normethadone, noscapine, pholcodine, dextromethorphan, thebacon,dimemorfan, acetyldihydrocodone, benzonatate, benproperine, clobutinol,isoaminile, pentoxyverine, oxolamine, oxeladin, clofedanol, pipazetate,bibenzonium bromide, butamirate, fedrilate, zipeprol, dibunate,droxypropine, prenoxdiazine, dropropizine, cloperastine, meprotixol,piperidione, tipepidine, morclofone, nepinalone, levodropropizine, ordimethoxanate.

In another embodiment, the active pharmaceutical ingredient may be asubstance with abuse potential that presents a safety risk. Such activedrug substance may include: 1-(1-phenylcyclohexyl)pyrrolidine,1-(2-phenylethyl)-4-phenyl-4-acetoxypiperidine,1-[1-(2-thienyl)-cyclohexylpiperidine,1-[1-(2-thienyl)cyclohexyl]pyrrolidine,1-methyl-4-phenyl-4-propionoxy-piperidine, 1-phenylcyclohexylamine,1-piperidinocyclohexanecarbonitrile, 2,5-dimethoxy-4-ethylamphetamine,2,5-dimethoxyamphetamine, 2C-B-(4-bromo-2,5-dimethoxypenethylamine),2C-D (2,5-dimethoxy-4-methylphenethylamine), 2C-I(4-iodo-2,5-dimethoxy-phenethylamine), 2C-T-2(2,5-dimethoxy-4-ethylthiophenethylamine), 2C-T-4(2,5-dimethoxy-4-isopropylthiophenethylamine), 2C-T-7(2,5-dimethoxy-4-(n)-propylthiophenethylamine),3,4-methylene-dioxymethamphetamine, 3,4,5-trimethoxyamphetamine,3,4-methylenedioxyamphetamine, 3,4-methylenedioxy-N-ethyl amphetamine,3-methylfentanyl, 3-methylthiofentanyl,4-brorno-2,5-dimethoxyamphetamine, 4-bromo-2,5-dimethoxyphenethylamine,4-methoxyamphetamine, 4-methyl-2,5-dimethoxyamphetamine,4-methylaminorex (cis isomer), 5-MeO-DIPT(5-methoxy-N,N-diisopropyltryptamine), 5-MeO-DMT(5-methoxy-N,N-dimethyltryptamine),5-methoxy-3,4-methylenedioxyamphetamine, acetorphine, acetorphine,acetyl-alpha-methylfentanyl, acetyl-alpha-methylfentanyl,acetyldihydrocodone, acetylmethadol, acetylmethadol, alfentanil,allobarbital, allylprodine, alphacetylmethadol exceptlevo-alphacetylmethadol, alpha-ethyltryptamine, alphameprodine,alphamethadol, alphamethadol, alpha-methylfentanyl,alpha-methylthiofentanyl, alphaprodine, alprazolam, amfepramon,amfetaminil, amineptin, aminorex, amobarbital, amphetamine,dextroamphetamine, amilnitrite (all isomers of the amyl group), anabolicsteroids, anileridine, aprobarbital, barbital, barbituric acidderivative, BDB (3,4-methylenedioxyphenyl)-2-butanamine), benzethidin,benzethidine, benzoylecgonine, benzphetamine, benzphetamine,benzylmethylcetone, benzylmorphine, betacetylmethadol,beta-hydroxy-3-methylfentanyl, beta-hydroxyfentanyl, betameprodine,betameprodine, betamethadol, betaprodine, bezitramide, bezitramide,boldenone, brolamfetamine, bromazepam, brotizolam, bufotenine,buprenorphine, butabarbital, butalbital, butobarbital, butorphanol, BZP(A2)(1-benzylpiperazin), camazepam, cannabis, carfentanil, catha edulis,cathine, cathinone, chloral betaine, chloral hydrate, chlordiazepoxide,chlorhexadol, chlorotestosterone (same as clostebol), chlorphentermine,clobazam, clonazepam, clonitazene, clonitazene, clorazepate,clortermine, clostebol, clotiazepam, cloxazolam, coca leaves, cocaine,codeine, codeine and isoquinoline alkaloid, codeine methylbromide,codeine-N-oxide, codoxime, cyclobarbital (hexemal NFN), cyprenorphine,dehydrochlormethyltestosterone, delorazepam, desomorphine,dexamfetamine, dexfenfluramine, dexmethylphenidate, dextromoramide,dextropropoxyphene, diacetylmorphine, diampromide, diazepam,dichloralphenazone, diethylpropion, diethylthiambutene,diethyltryptamine, difenoxin, dihydrocodone, dihydroetorphine,dihydromorphine, dihydrotestosterone, dimenoxadol, dimepheptanol,dimethylthiambutene, dimethyltryptamine, dioxaphetyl butyrate,diphenoxylate, dipipanone, diprenorphine, dronabinol, drostanolone,drotebanol, ecgonine, estazolam, ethchlorvynol, ethinamate, ethylloflazepate, ethylestrenol, ethylmethylthiambutene, ethylmorphine,ethylmorphine, eticyclidine, etilamfetamine, etonitazene, etorphine,etoxeridine, etryptamine, fencamfamin, fenethylline, fenetylline,fenfluramine, fenproporex, fentanyl, fludiazepam, flunitrazepam,fluoxymesterone, flurazepam, formebolone, fungi and spores of thespecies psilocybe semilanceata, furethidine, gamma hydroxybutyric acid,glutethimide, halazepam, haloxazolam, heroine, hydrocodone, hydrocodone& isoquinoline alkaloid, hydromorphinol, hydromorphone,hydroxypethidine, ibogaine, isobutyl nitrite, isomethadone, ketamine,ketazolam, ketobemidone, levamfetamine, levo-alphacetylmethadol,levo-methamphetamine, levomethorphan, levomoramide, levophenacylmorphan,levorphanol, lis dexamfetamine, loprazolam, lorazepam, lormetazepam,lysergic acid, lysergic acid amide, lysergic acid diethylamide,marijuana, mazindol, MBDN(N-methyl-1-(3,4-methylenedioxyphenyl)-2-butanamine), mCPP(1-(3-chlorphenyl)piperazine), mebutamate, mecloqualone, medazepam,mefenorex, MeOPP (1-(4-methoxyphenyl)piperazine), meperidine, meperidineintermediate, meprobamate, mescaline, mesocarb, mesterolone,metamfetamine, metazocine, methadone, methadone intermediate,methamphetamine, methandienone, methandrolone, methandriol,methandrostenolone, methaqualone, methcathinone, methenolone,methohexital, methyldesorphine, methyldihydromorphine, methylphenidate,methylphenobarbital (mephobarbital), methyltestosterone, methyprylone,metopone, mibolerone, midazolam, modafinil, moramide-intermediate,morpheridine, morphine, morphine methylbromide, morphinemethylsulfonate, morphine-N-oxide, myrophine, N,N-dimethylamphetamine,nabilone, nalorphine, nandrolone, N-ethyl-1-phenylcyclohexylamine,N-ethyl-3-piperidyl benzilate, N-ethylamphetamine,N-hydroxy-3,4-methylenedioxyamphetamine, nicocodeine, nicocodine,nicodicodine, nicomorphine, nimetazepam, nitrazepam,N-methyl-3-piperidyl benzilate, noracymethadol, norcodeine, nordiazepam,norethandrolone, norlevorphanol, normethadone, normorphine, norpipanone,norpipanone, opium, oxandrolone, oxazepam, oxazolam, oxycodone,oxymesterone, oxymetholone, oxymorphone, para-fluorofentanyl, parahexyl,paraldehyde, pemoline, pentazocine, pentobarbital, petrichloral, peyote,phenadoxone, phenampromide, phenazocine, phencyclidine, phendimetrazine,phenmetrazine, phenobarbital, phenomorphan, phenoperidine, phentermine,phenylacetone, pholcodine, piminodine, pinazepam, pipradrol,piritramide, PMMA (paramethyxymethyl amphetamine), prazepam,proheptazine, properidine, propiram, psilocybine, psilocine,pyrovalerone, quazepam, racemethorphane, racemoramide, racemorphane,remifentanil, salvia divinorum, salvinorin A, secobarbital,secobarbital, sibutramine, SPA, stanolone, stanozolol, sufentanil,sulfondiethylmethane, sulfonethylmethane, sulfonmethane, talbutal,temazepam, tenamfetamine, testolactone, testosterone,tetrahydrocannabinols, tetrazepam, TFMPP(1-(3-triflourmethylphenyl)piperazine), thebacon, thebaine, thiamylal,thiofentanyl, thiopental, tiletamine and zolazepam in combination,tilidine, trenbolone, triazolam, trimeperidine, vinbarbital, zaleplon,zipeprol, zolpidem, or zopiclone.

Other suitable examples of active drug substances suitable for use inthe pharmaceutical compositions described herein include, for example,alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine,bezitramide, buprenorphine, butorphanol, clonitazene, codeine,cyclazocine, desomorphine, dextromoramide, dezocine, diampromide,dihydrocodone, dihydromorphine, dimenoxadol, dimepheptanol,dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine,ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene,fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine,isomethadone, dextropropoxyphene, ketobemidone, levallorphan,levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol,metazocine, methadone, metopon, morphine, morphine 6-glucuronide,morphine 3-glucuronide, myrophine, nalbuphine, narcine, nicomorphine,norlevorphanol, normethadone, nalorphine, normorphine, norpipanone,opium, oxycodone, oxycodeine, oxymorphone, papaveretum, pentazocine,phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine,piritramide, proheptazine, promedol, properidine, propiram,propoxyphene, sufentanil, tilidine, tramadol, thebaine,levo-alphacetylmethadol (LAAM), remifentanil, carfentanyl, ohmefentanyl,MPPP, prodine, PEPAP, levomethorphan, etorphine, lefetamine, loperamide,diphenoxylate, or pethidine.

Other examples of active drug substances suitable for use in thepharmaceutical compositions described herein include anabolic steroids,cannabis, cocaine, or diazepam.

In another embodiment, the active drug substance comprises thetherapeutic classes including non-steroidal anti-inflammatory substancesor antirheumatic active drug substances.

In other embodiments, the active drug substance comprises analgesics,opioids, antipyretics, anaesthetics, antimigraine agents,antiepileptics, anti-parkinson agents, dopaminergic agents,antipsychotics, anxiolytics, sedatives, antidepressants,psychostimulants agents, dopamine, noradrenaline, nicotinic,alfa-adrenergic, serotonin, H3 antagonists used for ADHD or nootropicsagents used in addictive disorders.

In other embodiments, the active drug substance comprises therapeuticclasses including anaesthetics, centrally acting analgesics,sedative-hypnotics, anxiolytics, appetite suppressants, decongestants,antitussives, antihistamines, antiemetics, antidiarrheals, and drugsused to treat narcolepsy, or attention deficit hyperactivity disorder.

In another embodiment, the active drug substance is associated withabuse syndromes and the active drug substance may, for example, beselected from opioids, CNS depressants, CNS stimulants, cannabinoids,nicotine-like compounds, glutamate antagonists, or N-methyl-D-aspartate(NMDA) antagonists.

In another embodiment, the active drug substance is an analgesic.Examples of analgesics suitable for use in the pharmaceuticalcompositions described herein include, for example, opioids, naturalopium alkaloids, morphine, opium, hydromorphone, nicomorphine,oxycodone, dihydrocodone, diamorphine, tapentadol, papaveretum, codeine,phenylpiperidine derivatives, ketobemidone, pethidine, fentanyl,diphenylpropylamine derivatives, dextromoramide, piritramide,dextropropoxyphene, bezitramide, methadone, benzomorphan derivatives,pentazocine, phenazocine, oripavine derivatives, buprenorphine,morphinan derivatives, butorphanol, nalbuphine, tilidine, tramadol,dezocine, salicylic acid and derivatives, acetylsalicylic acid,aloxiprin, choline salicylate, sodium salicylate, salicylamide,salsalate, ethenzamide, morpholine salicylate, dipyrocetyl, benorilate,diflunisal, potassium salicylate, guacetisal, carbasalate calcium,imidazole salicylate, pyrazolones, phenazone, metamizole sodium,aminophenazone, propyphenazone, nifenazone, anilides, paracetamol,phenacetin, bucetin, propacetamol, other analgesics and antipyreticssuch as, for example, rimazolium, glafenine, floctafenine, viminol,nefopam, flupirtine, or ziconotide.

In another embodiment, the active drug substance is an opioid. Where anopioid is included as an active drug substance, the opioid may comprisenaturally occurring opioids, synthetic opioids, or semisyntheticopioids.

In other embodiment, the active drug substance comprises amfetamine,dexamfetamine, lisdexamfetamine, metamfetamine, methylphenidate,dexmethylphenidate, or combinations thereof.

In another embodiment, the pharmaceutical compositions disclosed hereinincludes an opioid, the opioid is selected from buprenorphine, codeine,dextromoramide, dihydrocodone, fentanyl, hydrocodone, hydromorphone,morphine, pentazocine, oxycodeine, oxycodone, oxymorphone,norhydrocodone, noroxycodone, morphine-6-glucuronode, tramadol,tapentadol, or dihydromorphine.

Where an opioid is used as an active drug substance, the opioid may bepresent in any of its crystalline, polymorphous, semi-crystalline, andamorphous or polyamorphous forms. Furthermore, in another embodiment, anopioid used as an active drug substance may be present in one or moreforms selected from its crystalline, polymorphous, semi-crystalline, oramorphous or polyamorphous forms.

Some embodiments of the pharmaceutical compositions disclosed hereininclude an opioid as an active drug substance, the active drug substanceis selected from morphine, oxycodone, hydrocodone, hydromorphone,norhydrocodone, oxymorphone, noroxycodone, morphine-6-glucuronode andpharmaceutically acceptable salts thereof, including oxycodonehydrochloride, hydrocodone bitartrate, hydromorphone hydrochloride ormorphine sulphate pentahydrate.

In other embodiments, the pharmaceutical compositions as describedherein are suitable for use for water soluble as well as slightlysoluble or insoluble active drug substances.

In another embodiment, all of the above mentioned active drug substancesmay also be in the form of pharmaceutically acceptable salts, unchargedor charged molecules, molecular complexes, solvates, or anhydratesthereof, and, if relevant, single isomers, enantiomers, racemicmixtures, or mixtures thereof.

In another embodiment, the pharmaceutical compositions described hereinmay comprise pharmaceutically acceptable salts of any of the abovementioned active drug substances.

In another embodiment, the active pharmaceutical ingredient ishydrocodone or oxycodone or a pharmaceutically acceptable salt form ofeither hydrocodone or oxycodone. Pharmaceutically acceptable salts formsare those formed by contacting hydrocodone or oxycodone free base with asuitable acid in a suitable solvent under suitable conditions that willform a form of hydrocodone or oxycodone acid addition salt. Suitableacids include hydrochloric acid, camphorsulfonic acid, hydrobromic acid,sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalicacid, succinic acid, tartaric acid, mandelic acid, malic acid, salicylicacid, fumaric acid, lactic acid, citric acid, glutamic acid, and/oraspartic acid.

The term “pharmaceutically acceptable salts” of an active drug substanceincludes alkali metal salts such as, for example, sodium or potassiumsalts, alkaline earth metal salts such as, for example, calcium andmagnesium salts, and salts with organic or inorganic acid such as, forexample, hydrochloric acid, hydrobromic acid, nitric acid, sulfuricacid, phosphoric acid, citric acid, formic acid, maleic acid, succinicacid, tartaric acid, methanesulphonic acid, toluenesulphonic acid etc.In another embodiment, pharmaceutically acceptable opioid salts cancomprise sulphate salts, hydrochloride salts, and bitartrate salts.

The concentration of the active pharmaceutical ingredient in thepharmaceutical composition described herein depends on the specificactive pharmaceutical ingredient substance, the disease to be treated,the condition of the patient, the age, and gender of the patient, etc.The active pharmaceutical ingredient may be known and a person skilledin the art will be able to find information as to the dosage of eachactive drug substance and, accordingly, will know how to determine theamount of each active drug substance in the pharmaceutical composition.

The active pharmaceutical ingredient may be a new chemical entity forwhich the amount of information is limited. In such cases, the dosagehas to be evaluated based on available preclinical and/or clinical data.

In some embodiments described herein, the pharmaceutical compositioncomprises a dosage form comprising a soft capsule shell or a hardcapsule shell.

In one embodiment, the soft capsule shell has the composition of Table2, including all possible iterations of the specified ranges thatprovide 100% for the total weight percentage, including or excluding theoptional colorings, flavorings, or excipients.

TABLE 2 Exemplary soft gelatin capsule composition Exemplary WeightComponent Component Percentage (%) Film-forming polymer Gelatin 20-36(Gelatin) Plasticizer Glycerol 10-30 Solvent Water 20-70 Opacifier(optional) Titanium dioxide 0.5-1.5 Coloring agent (optional) Various0.05-0.1  TOTAL 100%

Film-former polymers that are useful for creating soft capsules aregelatin, hydroxypropylmethylcellulose (HPMC) or carrageenan (e.g., iotacarrageenan and kappa carrageenan). In one aspect of the enteric softcapsule shell described herein, the film-forming polymer is gelatin. Inanother aspect of the enteric soft capsule shell described herein, thefilm-forming polymer is carrageenan.

Plasticizers that are useful for creating soft capsules as describedherein are glycerol, sorbitol, polyethylene glycols, or combinationsthereof. The weight ratio between the film-forming polymer, plasticizer,and solvent is adjusted so that the gel mass is flowable and not tooviscous, and can be made into soft capsules using rotary dieencapsulation methods.

In one embodiment, the enteric soft capsule shell has the exemplarycomposition shown in Table 3.

TABLE 3 Exemplary Soft Capsule Shell Composition Percent Componentweight (%) Gelatin 43   Glycerol 20   Titanium dioxide (optional) 0.7Coloring agent (optional) 0.1 Water 36.2  TOTAL 100% Final pH ~4-7 Ratiototal plasticizer to gelatin 20:43 (0.46:1) Water content in dried softcapsule shell: 8-15%

In one embodiment described herein, the soft capsule comprises about 43%of at least one film-forming polymer; about 20% of at least oneplasticizer; about 36% water; optionally, about 0.7% titanium dioxide;and optionally, about 0.1% of at least one coloring agent.

In one embodiment described herein, the enteric soft capsule describedherein comprises a composition of about 3% to about 10% film formingpolymer (e.g., a composition of carrageenan); about 10% to about 30%filler; about 10% to about 30% plasticizer; and about 30% to about 70%solvent.

In one embodiment, the weight percentage range of film-forming polymerof the soft capsule described herein is about 35% to about 45%,including all integers within the specified range. In one aspect, thefilm-forming polymer weight percentage is about 38%. In another aspect,the film-forming 1 polymer weight percentage is about 42%. In anotheraspect, the film-forming polymer weight percentage is about 44%.

In one embodiment, the weight percentage range of film-forming polymerof the soft capsule described herein is about 3% to about 15%, includingall integers within the specified range. In one aspect, the film-formingpolymer weight percentage is about 3%. In one aspect, the film-formingpolymer weight percentage is about 5%. In one aspect, the film-formingpolymer weight percentage is about 7%. In one aspect, the film-formingpolymer weight percentage is about 10%. In one aspect, the film-formingpolymer weight percentage is about 12%.

In one embodiment, the weight percentage range of plasticizer is about15% to about 22%, including all iterations of integers with thespecified range. In one aspect, the plasticizer weight percentage isabout 17%. In another aspect, the plasticizer weight percentage is about18.5%. In another aspect, the plasticizer weight percentage is about20%.

In one embodiment, the weight percentage ratio range of plasticizer tofilm-forming polymer is about 0.33:1 to about 0.56:1, including alliterations of iterations of ratios with the specified range. In oneembodiment, the weight percentage ratio range of plasticizer tofilm-forming polymer is about 0.38:1. In one embodiment, the weightpercentage ratio range of plasticizer to film-forming polymer is about0.42:1. In one embodiment, the weight percentage ratio range ofplasticizer to film-forming polymer is about 0.46:1. In one embodiment,the weight percentage ratio range of plasticizer to film-forming polymeris about 0.52:1.

In one aspect, soft capsules are made using a rotary die apparatus asdescribed in U.S. Pat. Nos. 5,459,983; 5,146,730; and 6,482,516, each ofwhich are incorporated by reference herein for such teachings.

Another embodiment described herein includes a process of manufacturingsoft capsules comprising the pharmaceutical composition as describedherein. The process includes preparing a gel mass composition comprisinga film-forming, water-soluble polymer, an appropriate plasticizer, andsolvent; casting the gel mass into films or ribbons usingheat-controlled drums or surfaces; and manufacturing a soft capsulecomprising a matrix fill using rotary die technology.

The thickness of the films or ribbons that form the soft capsule shellis from about 0.010 inches (≈0.254 mm) to about 0.050 inches (≈1.27 mm),including all integers within the specified range. The shell thicknesscan be about 0.010 inch (≈0.254 mm), about 0.015 inch (≈0.381 mm), about0.02 in (≈0.508 mm), about 0.03 in (≈0.762 mm), about 0.04 in (≈4.02mm), or about 0.05 in (≈1.27 mm). In one embodiment, the thickness isabout 0.02 inches (≈0.508 mm) to about 0.040 inches (≈1.02 mm). In oneembodiment, the shell thickness is about 0.028 inches (≈0.711 mm). Inanother embodiment, the shell thickness is about 0.033 inches (≈0.838mm). In another embodiment, the shell thickness is about 0.038 inches(≈0.965 mm).

In one embodiment described herein, the soft capsule shell describedherein, encapsulates a matrix fill as described herein. In anotherembodiment described herein, the soft capsule shell and encapsulatedmatrix fill comprises an outer dimension from about 2 oval to about 30oval including all iterations of capsule size within the specified range(e.g., 2 oval, 3 oval, 4 oval, 5 oval, 6 oval, 7 oval, 8 oval, 10 oval,12 oval, 16 oval, 20, or 30 oval). In another embodiment describedherein, the soft capsule shell and encapsulated matrix fill comprises anouter dimension from about 2 round to about 28 round including alliterations of capsule size within the specified range (e.g., 2 round, 3round, 4 round, 5 round, 6 round, 7 round, 8 round, 10 round, 12 round,16 round, 20 round or 28 round). In another embodiment described herein,the soft capsule shell and encapsulated matrix fill comprises an outerdimension from about 2 oblong to about 22 oblong including alliterations of capsule size within the specified range (e.g., 2 oblong, 3oblong, 4 oblong, 5 oblong, 6 oblong, 7 oblong, 8 oblong, 10 oblong, 11,oblong, 12 oblong, 14 oblong, 16 oblong, 20 oblong, or 22 oblong).Dimension specifications of soft capsules and tablets are known to thoseskilled in the art. See Remington's Essentials of Pharmaceutics,Pharmaceutical Press Publishing Company, London, UK, 1st Edition, 2013,which is incorporated by reference herein for such teachings.

In another embodiment described herein, the pharmaceutical compositioncomprises an enteric soft capsule shell comprising a matrix fillcomprising an active pharmaceutical ingredient.

Enteric soft capsules are described in International Patent ApplicationPublication No. WO 2004/030658; U.S. Patent Application Publication No.US 2006/0165778; and U.S. Pat. No. 8,685,445, each of which isincorporated by reference herein for such teachings. The enteric softcapsule shell may comprise one or more film forming polymers, one ormore enteric acid-insoluble polymers, one or more plasticizers, one ormore alkali-neutralizing agents, one or more solvents, optionally one ormore colorants, and optionally one or more flavorings or otherconventionally accepted pharmaceutical excipients or additives.

Film-former polymers that are useful for creating enteric soft capsulesare gelatin, hydroxypropylmethylcellulose (HPMC) or carrageenan (e.g.,iota carrageenan and kappa carrageenan). In one aspect of the entericsoft capsule shell described herein, the film-forming polymer isgelatin. In another aspect of the enteric soft capsule shell describedherein, the film-forming polymer is carrageenan.

Examples of enteric, acid-insoluble polymers are acrylic andmethacrylate acid copolymers, cellulose acetate phthalate (CAP),cellulose acetate butyrate, hydroxypropylmethylcellulose phthalate(HPMCP), alginic acid salts such as sodium or potassium alginate, orshellac. Poly(methacylic acid-co-methyl methacrylate) anionic copolymersbased on methacrylic acid and methyl methacrylate are particularlystable and are preferred in some embodiments. Poly(meth)acrylates(methacrylic acid copolymer), available under the trade name EUDRAGIT®(Evonik Industries AG, Essen, Germany), are provided as powder oraqueous dispersions. In one aspect, the methacrylic acid copolymer canbe EUDRAGIT® L 30 D-55; EUDRAGIT® L 100-55; EUDRAGIT® L 100; EUDRAGIT® L12.5; EUDRAGIT® S 100; EUDRAGIT® S 12.5; EUDRAGIT® FS 30 D; EUDRAGIT® E100; EUDRAGIT® E 12.5; EUDRAGIT® E PO; EUDRAGIT® RL 100; EUDRAGIT® RLPO; EUDRAGIT® RL 30 D; EUDRAGIT® RL 12.5; EUDRAGIT® RS 100; EUDRAGIT® RSPO; EUDRAGIT® RS 30 D; EUDRAGIT® RS 12.5; EUDRAGIT® NE 30 D; EUDRAGIT®NE 40 D; EUDRAGIT® NM 30 D; or other poly(meth)acrylate polymers. In oneaspect, the enteric polymer is EUDRAGIT® L 100, a methacrylic acidcopolymer, Type A. Acid-insoluble polymer specifications are detailed inthe United States Pharmacopoeia and in various monographs.

Plasticizers that are useful for creating enteric soft capsules asdescribed herein are glycerol, sorbitol, polyethylene glycol, citricacid, citric acid esters, such as tri-ethyl citrate, or combinationsthereof. The weight ratio between the film-forming polymer, the entericacid-insoluble polymer, and plasticizer is adjusted so that the gel massis flowable and not too viscous, and can be made into soft capsulesusing rotary die encapsulation methods.

In one embodiment, enteric soft capsule shell compositions can be madeby dissolving the enteric acid-insoluble polymer in an aqueous solutionof an alkali neutralizing agent such as ammonia, sodium hydroxide,potassium hydroxide, or liquid amines such as tri-ethanol amine orethylene diamine. The amount of alkali is adjusted to give a final pHvalue of the gel mass less than or equal to about pH 9.0. In oneembodiment, the final pH does not exceed 8.5. The volatile alkalineutralizing agent, ammonia is preferred. The film-forming polymer canthen be combined with the plasticizer and solvent and then blended withthe acid-insoluble gel to make a final homogeneous mix in aheat-controlled vessel and can be degassed by using vacuum. The fugitiveammonia evaporates during degassing. Using the foregoing process, thealkali concentrations do not require an additional step such as heatingor neutralizing with acid in order to neutralize the gel mass.

In another embodiment described herein, an enteric soft capsule shellcan be made by using an aqueous dispersion of the acid-insoluble polymerby adding alkaline materials such as ammonium, sodium, or potassiumhydroxides, other alkalis, or a combination thereof that will cause theenteric acid-insoluble polymer to dissolve. The plasticizer-wetted,film-forming polymer can then be mixed with the solution of theacid-insoluble polymer. In one embodiment, enteric acid-insolublepolymers in the form of salts of the above-mentioned bases or alkaliscan be dissolved directly in water and mixed with theplasticizer-wetted, film-forming polymer.

In one embodiment, an enteric soft capsule shell has the composition ofTable 4, including all possible iterations of the specified ranges thatprovide 100% for the total weight percentage, including or excluding theoptional, excipients, opacifiers, colorants, and flavorings.

TABLE 4 Exemplary Enteric Soft Capsule Shell Composition ExemplaryComposition Component Component Range (%) Film-forming polymer Gelatin20-36 Enteric, acid insoluble Methacrylic Acid  8-20 polymer CopolymerPlasticizer Glycerol, Triethyl citrate 15-22 Alkali neutralizing agentsNH₄OH (30%), NaOH 1-5 Solvent Water 20-40 Opacifier Titanium Dioxide  1-7.5 Colorant (optional) Various 0.05-1   Flavoring (optional)Various 0.05-2   Excipients (optional) Various 1-5

In one embodiment, an enteric soft capsule shell comprises a compositionof about 30% film forming polymer (e.g., gelatin); about 10% enteric,acid insoluble polymer; about 20% plasticizer; about 1% alkalineutralizing agent; and about 37% solvent.

In one embodiment described herein, the enteric soft capsule describedherein comprises a composition of about 3% film forming polymer (e.g., acomposition of carrageenan); about 10% enteric, acid insoluble polymer;about 10% filler; about 10% plasticizer; about 1% alkali neutralizingagent; about 2% sealant; and about 60% solvent.

In one embodiment, the weight percentage range of total polymer content(i.e., film forming polymer and enteric acid-insoluble polymer) of theenteric soft capsule described herein is about 30% to about 45%,including all integers within the specified range. In anotherembodiment, the weight percentage range of total polymer content (i.e.,film forming polymer and enteric acid-insoluble polymer) of the entericsoft capsule described herein is about 9% to about 35%, including allintegers within the specified range. In one aspect, the total polymerweight percentage is about 40%. In another aspect, the total polymerweight percentage is about 42%. In another aspect, the total polymerweight percentage is about 45%. In another aspect, the total polymerweight percentage is about 38%. In another aspect, the total polymerweight percentage is about 12%. In another aspect, the total polymerweight percentage is about 16%.

In one embodiment, the weight percentage range of total plasticizer isabout 15% to about 22%, including all iterations of integers with thespecified range. In one aspect, the total plasticizer weight percentageis about 19%. In another aspect, the total plasticizer weight percentageis about 17.7%. In another aspect, the total plasticizer weightpercentage is about 18.9%. In another aspect, the total plasticizerweight percentage is about 19.3%.

In one embodiment, the alkali neutralizing-agent is ammonia (ammoniumhydroxide; 30% w/v) that is added to comprise a weight percentage ofabout 1 to about 5% of the total enteric soft capsule composition. Inone aspect, 30% w/v ammonia is added to comprise a weight percentage ofabout 2%. In another aspect, 30% w/v ammonia is added to a weightpercentage of about 1.7%. In one aspect, ammonia is added to provide afinal pH of about 9 in the enteric soft capsule composition. In anotheraspect, ammonia is added to provide a final pH of about 8.5 in theenteric soft capsule composition. In another aspect, after the capsulesare filled and dried, the ammonia concentration is substantiallyreduced, owing to the fugitive nature of the volatile alkali. In oneaspect, practically all of the ammonia is evaporated except for ammoniumions comprising salts with other moieties in the composition.

In one embodiment, the weight ratio range of film forming polymer toenteric acid insoluble polymer (film forming: enteric) is about 25:75(≈0.33) to about 40:60 (≈0.67) (i.e., ≈0.33-0.67), including alliterations of ratios within the specified range. In one aspect, theratio of film forming polymer to enteric acid insoluble polymer is about30:70 (≈0.43). In another aspect, the ratio of film forming polymer toenteric acid insoluble polymer is about 28:72 (≈0.38).

In another embodiment described herein, the weight ratio range of filmforming polymer (i.e., total carrageenan composition) to enteric acidinsoluble polymer (film forming: enteric) in the enteric soft gelcomposition is about 3:9 (≈0.3) to about 4:3 (≈4.3) (i.e., ≈0.3-1.3),including all ratios within the specified range. In some aspects, theratio of film forming polymer to enteric acid insoluble polymer in thegel mass is about 1:3 (≈0.33), about 1:2.5 (≈0.4), about 1:2 (≈0.5),about 1:1.6 (≈0.6), about 1:1.25 (≈0.8), about 1:1 (≈1), about 1.1:1(≈1.1), about 1.21 (≈1.2), or about 1.3:1 (≈1.3). In one aspect, theratio of film forming polymer to enteric acid insoluble polymer in thegel mass is about 1:2.5 (≈0.4). In another aspect, the ratio of filmforming polymer to enteric acid insoluble polymer is about 1:3 (≈0.3).

In one embodiment, the weight ratio of total plasticizer to film formingpolymer is about 20:40 to 21:30 (i.e., ≈0.5-0.7) including alliterations of ratios within the specified range. In one aspect, theweight ratio of total plasticizer to film forming polymer is about 20:40(≈0.5). In another aspect, the weight ratio of total plasticizer to filmforming polymer is about 21:30 (≈0.7). In another aspect, the weightratio of total plasticizer to film forming polymer is about 19:29(≈0.65). In another aspect, the weight ratio of total plasticizer tofilm forming polymer is about 19.3:29.2 (≈0.66).

In one embodiment, the weight ratio of total plasticizer to enteric acidinsoluble polymer is about 1:1 to about 2:1 (≈1-2), including alliterations of ratios within the specified range. In one aspect, theweight ratio of total plasticizer to enteric acid insoluble polymer isabout 11:10 (≈1.1). In another aspect, the weight ratio of totalplasticizer to enteric acid insoluble polymer is about 14:10 (≈1.4). Inanother aspect, the weight ratio of total plasticizer to enteric acidinsoluble polymer is about 17:10 (≈1.7). In another aspect, the weightratio of total plasticizer to enteric acid insoluble polymer is about20:10 (≈2). In another aspect, the weight ratio of total plasticizer toenteric acid insoluble polymer is about 19.3:11.2 (≈1.73).

In one embodiment, the weight ratio range of total plasticizer to totalpolymer (film forming and enteric acid insoluble polymer) is about 18:45to about 20:40 (i.e., ≈0.40-0.5), including all iterations of ratioswithin the specified range. In one aspect, the weight ratio range oftotal plasticizer to total polymer is about 18:45 (≈0.40). In anotheraspect, the weight ratio range of total plasticizer to total polymer isabout 19:40 (≈0.475). In another aspect, the weight ratio range of totalplasticizer to total polymer is about 20:40 (≈0.5). In another aspect,the weight ratio range of total plasticizer to total polymer is about19.3:40.4 (≈0.477).

In one embodiment, the solvent comprises about 20% to about 40% of theenteric soft capsule composition, including all integers within thespecified range. In one embodiment, the solvent is water. The quantityof water in the composition varies depending on the quantities of theother ingredients. For example, the quantity of opacifier, colorant,flavoring, or other excipients can change the percentage of waterpresent the composition. In one embodiment, the weight percentage ofwater is as much as suffices to bring the total weight percentage to100% (i.e., quantum sufficiat; q.s.). In another embodiment, the watercomprises about 20%, about 25%, about 30%, about 35%, or about 40% ofthe enteric soft capsule composition. In another embodiment, watercomprises about 35% to about 40% of the enteric soft capsulecomposition. In one embodiment, water comprises about 37% of thecomposition.

In one embodiment, the final moisture (water) content of the entericsoft capsule is from about 8% to about 15%, including all integerswithin the specified range. In another embodiment, the moisture contentis about 8% to about 12%, including all integers within the specifiedrange. In one aspect, the final moisture content is about 8%. In oneaspect, the final moisture content is about 9%. In one aspect, the finalmoisture content is about 10%. In one aspect, the final moisture contentis about 11%. In another aspect, the final moisture content is about12%.

In one embodiment, the enteric soft capsule shell has the exemplarycomposition shown in Table 5.

TABLE 5 Exemplary Enteric Soft Capsule Shell Composition ComponentPercent weight Gelatin  29.2 Methacrylic Acid Copolymer  11.2(EUDRAGIT ® L 100) Glycerol  18.0 Triethyl citrate  1.3 Ammoniumhydroxide  1.7 Titanium dioxide  1.5 Water  37.1 TOTAL 100% Final pH ~4-9 Total polymer % weight(gelatin + enteric)  40.4% Gelatin % wt oftotal polymer (gelatin +  72.4% enteric) Enteric % wt of total polymer(gelatin +  27.6% enteric) Ratio of Enteric to Gelatin  11.2:29.2 (0.38)Total plasticizer % weight (glycerol +  19.3% triethyl citrate) Ratio oftotal plasticizer to total polymer  19.3:40.4 (0.48) Ratio totalplasticizer to gelatin  19.3:29.2 (0.66) Ratio total plasticizer toenteric  19.3:11.2 (1.73) Water content in dried enteric soft capsule: 8-15%

In one embodiment, the enteric soft capsule shell comprises about 30%gelatin; about 10% poly(methyl) acrylate copolymer; about 18% glycerol;about 1% triethyl citrate; about 1.5% ammonia; about 37% water; andabout 1.5% titanium dioxide.

One embodiment described herein provides an enteric acid-insolublepolymer dispersed within the film-forming polymer gel mass that providesthe total soft gel composition with enteric acid-insoluble properties,at relatively low concentrations of the enteric acid-insoluble polymer(e.g., from about 8% to about 20% of the total wet gel mass composition)and without the need of excessive amounts of alkali, thus avoidingdenaturation or degradation of the film-forming polymer that can weakenthe integrity of the enteric soft capsule shell.

In some embodiments, the enteric soft capsule shell does not dissolve ordisintegrate in acids, such as 0.1 N hydrochloric acid or simulatedgastric fluid (ca. pH 1.2), despite the fact that the majority of theshell ingredients (i.e., greater than 50%) normally dissolve in, or aremiscible with, acids. In some embodiments, the enteric soft capsulesmade using the compositions described herein remain intact inhydrochloric acid or simulated gastric fluid for at least two hours andthe capsules readily release their contents upon shifting the pH of thesolution to ca. 6.8, such as that of simulated intestinal fluid. In oneaspect, the enteric soft capsule is resistant to dissolution at about pH1.2 for at least about 2 hours. In another aspect, the enteric softcapsule begins dissolution at pH of about 6.8 within about 10 min.

In another embodiment, the final enteric capsule composition providesfilms of increased strength without substantially compromising filmelasticity. Moreover, films made from the enteric soft capsulecompositions as described herein can be sealed at normal temperaturerange typically used for making traditional soft gel capsules. In oneaspect, enteric soft capsules are made using a rotary die apparatus asdescribed in U.S. Pat. Nos. 5,459,983; 5,146,730; and 6,482,516, each ofwhich are incorporated by reference herein for such teachings.

Another embodiment described herein includes a process of manufacturingenteric soft capsules comprising the pharmaceutical composition asdescribed herein. The process includes preparing a gel mass compositioncomprising a film-forming, water-soluble polymer and an entericacid-insoluble polymer and mixing with appropriate plasticizers andsolvent; casting the gel mass into films or ribbons usingheat-controlled drums or surfaces; and manufacturing a soft capsulecomprising a matrix fill using rotary die technology. The thickness ofthe films that form the enteric capsule and the dimensions of thecapsules are similar to those described herein.

In another embodiment, the capsule is a soft capsule comprising afilm-forming polymer that is stable at higher temperatures (e.g., about50° C. to about 80° C.). An exemplary film-forming polymer iscarrageenan (e.g., kappa or iota carrageenan). Exemplary, non-limitingsoft capsules comprising carrageenan are described in the InternationalPatent Application Publication No. WO 2003/061633; U.S. PatentApplication Publication No. US 2004/0052839; and U.S. Pat. Nos.6,949,256 and 7,887,838, each of which is incorporated by referenceherein for such teachings. In one aspect, soft capsules comprising afilm-forming polymer stable at high temperatures allow for matrix fillshaving a higher viscosity to be encapsulated minimizing the use ofadditional plasticizers. The increased encapsulation temperature, forexample, from about 50° C. to about 80° C. allows for a viscous matrixat a lower temperature to exhibit flowability for encapsulation by themethods described herein (e.g., rotary die encapsulation).

In another embodiment, the capsule shell is a hard capsule shell. In oneaspect, the hard capsule shell may comprise the abuse deterrent matricesdescribed herein. Any hard capsule shell, for example hard capsuleshells comprising gelatin, HPMC, or pullulan, including hard capsuleshells exhibiting enteric properties, maybe used with the abusedeterrent matrix fills described herein. Hard capsule shells are knownin the art and are described by Kathpalia et al., J. Adv. Pharm. Edu. &Res. 4(2): 165-177 (2014), which is incorporated by reference herein forthe specific teachings related to hard capsules.

Another embodiment is a controlled release pharmaceutical compositioncomprising a capsule shell encapsulating a matrix fill comprising one ormore active pharmaceutical ingredients, wherein the capsule shellcomprises one or more subcoatings, coatings, or topcoatings. Suitablecoatings may be adherence coatings, enteric coatings, moisture barriers,air or gas barriers, polymer coatings, colorings, flavors, writings, orcombinations thereof.

Exemplary polymers useful for coatings include cellulose acetatephthalate, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethylcellulose acetate succinate, polyvinyl acetate phthalate,polyvinyl alcohols, cellulose acetate trimellitate,carboxymethylcellulose, methacrylic acid copolymers such as, Eudragit L(polymethacrylic acid, methylmethacrylate, 1:1 ratio), or Eudragit S(polymethacrylic acid, methylmethacrylate, 1:2 ratio), shellac, zein, orcombinations thereof.

Suitable plasticizers include acetyl triethyl citrate, dibutylphthalate, tributyl citrate, triethyl citrate, acetyl tributyl citrate,propylene glycol, triacetin, polyethylene glycol, diethyl phthalate, orcombinations thereof.

Suitable solubilizers include sodium lauryl sulfate, sodium lauroylsarcosinate sodium dodecyl sulfate, polysorbate 20, polysorbate 80,other detergents or surfactants, or combinations thereof.

Anti-adherent agents serve to prevent potential agglomeration in acidmedia. Suitable anti-adherents include talc, magnesium stearate, calciumstearate, stearic acid, hydrogenated vegetable oils, polyethyleneglycols, fumed silica, silicon dioxide, or combinations thereof.

Pore-forming agents serve to create pores or channels in the entericcoating after administration to a human. Suitable pore-forming agentsinclude sodium chloride, potassium chloride, sucrose, sorbitol,mannitol, polyethylene glycols (PEG), propylene glycol, hydroxypropylcellulose, hydroxypropyl methylcellulose, polyvinyl alcohols,methacrylic acid copolymers, poloxamers, or combinations thereof.

Many conventional coating excipients are described in the art. See e.g.,Rowe et al., Eds. Handbook of Pharmaceutical Excipients, 7^(th) ed.Royal Pharmaceutical Society, UK (2012).

In one embodiment, adjusting the amount of coating and the ratio ofpolymer to other components allows for tuning the release profile of thedosage form.

Subcoats can be applied to the capsules prior to coating to preventshell-coat interactions and improve coating adhesion to the capsule.Exemplary subcoatings can comprise polyvinylpyrrolidone, polyvinylalcohols, hydroxpropyl methylcellulose, polyethylene glycol, oils, orcombinations thereof.

Coatings, top coatings, or subcoatings are applied to the exterior of acapsules using various methods know in the art. The coatings aretypically prepared as suspensions and sprayed on capsules in perforatedcoating pans through one or more spray nozzles at a specifictemperature. Coating solutions or dispersion may be applied at sprayrates between 100 and 400 g/min. The spray rate may be proportionatelyhigher for coatings with higher solid content and lower for more dilutedispersions. In one embodiment, capsules are coated using a pan coater.After the coating suspension is applied, the coated capsules are driedin the pan coater for a specific period of time at a specifictemperature.

Another embodiment described herein comprises a subcoating that isapplied prior to applying a coating. In one embodiment, the subcoatingcomprises hydroxpropyl methylcellulose, methylcellulose, ethylcellulose,or a combination thereof.

Another embodiment described herein comprises a coating that is applieddirectly on the exterior of the capsule. In one embodiment, the coatingcomprises polyvinyl alcohol, polyvinyl acetate hydroxpropylmethylcellulose, methylcellulose, ethylcellulose, or a combinationthereof.

Another embodiment described herein comprises a moisture barrier that isapplied as a coating. The moisture barrier can be applied directly tothe capsule or on top of a subcoating. In one embodiment the moisturebarrier comprises one or more polyvinyl alcohols and appropriatepharmaceutically acceptable excipients. In one embodiment the moisturebarrier comprises polyvinyl alcohol, sodium lauryl sulfate, glycerylmono-caprylate-caprate, and talc. In one aspect, the moisture barrieraids in preserving the cosmetic appearance of the dosage forms bypreventing dimpling, sticking, or other processing or storage inducedblemishes. In one embodiment, the polyvinyl alcohol coating comprisesOpadry® amb II, (Colorcon).

Without being bound by any theory, it is believed that a coating such aspolyvinyl alcohol applied to achieve about 10% to about 15% weight gainof the dosage form permits the dosage form to be annealed at atemperature of about 60° C. to about 75° C. for about 10 min to about 90min and slowly cooled to room temperature without causing cosmeticdefects such as dimpling, flattening, sticking, or other defects. It isbelieved that the coating protects the soft gelatin capsule and preventsit from becoming molten or tacky during the annealing and cooling steps.

In one embodiment, a coating is applied to the capsule dosage form toachieve about a 10% to about 15% weight gain to the dosage form. In oneaspect, the weight gain is about 10% to about 20%, including eachinteger within the specified range. In one aspect the weight gain isabout 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about20%. In another embodiment, a first coating is applied to achieve abouta 10% weight gain. In another embodiment, a second coating comprisingone or more coloring agents is applied to the first coated dosage formto achieved about a 5% weight gain, for a total coating weight gain ofabout 12% to about 15%. In one embodiment, about

The pharmaceutical composition described herein can comprise a soft orhard capsule comprising a matrix fill that is liquid, semi-solid, orsolid. Capsules prepared as described herein can contain a hydrophobicsolution, suspension, or lipid or lipophilic vehicle comprisingvegetable oils, shortening, or waxes, or combinations thereof. In someaspects described herein, the lipid or lipophilic vehicle may compriseone or more hydrophilic polymers, but as described herein, the vehicleis considered a lipid or lipophilic vehicle. The composition can beformulated to prevent interaction with the capsule shell components andrelease the pharmaceutical composition at a specified rate.

Additional pharmaceutical excipients useful for the pharmaceuticalcomposition as described herein include, for example, the following:acidifying agents (acetic acid, glacial acetic acid, citric acid,fumaric acid, hydrochloric acid, diluted hydrochloric acid, malic acid,nitric acid, phosphoric acid, diluted phosphoric acid, sulfuric acid,tartaric acid); alkalizing agents (ammonia solution, ammonium carbonate,diethanolamine, diisopropanolamine, potassium hydroxide, sodiumbicarbonate, sodium borate, sodium carbonate, sodium hydroxide,trolamine); antifoaming agents (dimethicone, simethicone); antimicrobialpreservatives (benzalkonium chloride, benzalkonium chloride solution,benzethonium chloride, benzoic acid, benzyl alcohol, butylparaben,cetylpyridinium chloride, chlorobutanol, chlorocresol, cresol,dehydroacetic acid, ethylparaben, methylparaben, methylparaben sodium,phenol, phenylethyl alcohol, phenylmercuric acetate, phenylmercuricnitrate, potassium benzoate, potassium sorbate, propylparaben,propylparaben sodium, sodium benzoate, sodium dehydroacetate, sodiumpropionate, sorbic acid, thimerosal, thymol); antioxidants (ascorbicacid, ascorbyl palmitate, butylated hydroxyanisole, butylatedhydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate,sodium formaldehyde sulfoxylate, sodium metabisulfite, sodiumthiosulfate, sulfur dioxide, tocopherol, tocopherols excipient);buffering agents (acetic acid, ammonium carbonate, ammonium phosphate,boric acid, citric acid, lactic acid, phosphoric acid, potassiumcitrate, potassium metaphosphate, potassium phosphate monobasic, sodiumacetate, sodium citrate, sodium lactate solution, dibasic sodiumphosphate, monobasic sodium phosphate); chelating agents (edetatedisodium, ethylenediaminetetraacetic acid and salts, edetic acid);coating agents (sodium carboxymethylcellulose, cellulose acetate,cellulose acetate phthalate, ethylcellulose, gelatin, pharmaceuticalglaze, hydroxypropyl cellulose, hydroxypropyl methylcellulose,hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer,methylcellulose, polyvinyl alcohol, polyvinyl acetate phthalate,shellac, sucrose, titanium dioxide, carnauba wax, microcrystalline wax,zein); colorants (caramel, red, yellow, black or blends, ferric oxide);complexing agents (ethylenediaminetetraacetic acid and salts (EDTA),edetic acid, gentisic acid ethanolamide, oxyquinoline sulfate);desiccants (calcium chloride, calcium sulfate, silicon dioxide);emulsifying and/or solubilizing agents (acacia, cholesterol,diethanolamine (adjunct), glyceryl monostearate, lanolin alcohols, mono-and di-glycerides, monoethanolamine (adjunct), lecithin, oleic acid(adjunct), oleyl alcohol (stabilizer), poloxamer, polyoxyethylene 50stearate, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil,polyoxyl 10 oleyl ether, polyoxyl 20 cetostearyl ether, polyoxyl 40stearate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate80, diacetate, monostearate, sodium lauryl sulfate, sodium stearate,sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate,sorbitan monostearate, stearic acid, trolamine, emulsifying wax);filtering aids (powdered cellulose, purified siliceous earth); flavorsand perfumes (anethole, benzaldehyde, ethyl vanillin, menthol, methylsalicylate, monosodium glutamate, orange flower oil, peppermint,peppermint oil, peppermint spirit, rose oil, stronger rose water,thymol, tolu balsam tincture, vanilla, vanilla tincture, vanillin);humectants (glycerol, hexylene glycol, sorbitol); plasticizers (e.g.,castor oil, diacetylated monoglycerides, diethyl phthalate, glycerol,mono- and di-acetylated monoglycerides, propylene glycol, triacetin,triethyl citrate); polymers (e.g., cellulose acetate, alkyl celluloses,hydroxyalkyl, acrylic polymers and copolymers); solvents (acetone,alcohol, diluted alcohol, amylene hydrate, benzyl benzoate, butylalcohol, carbon tetrachloride, chloroform, corn oil, cottonseed oil,ethyl acetate, glycerol, hexylene glycol, isopropyl alcohol, methylalcohol, methylene chloride, methyl isobutyl ketone, mineral oil, peanutoil, propylene carbonate, sesame oil, water for injection, sterile waterfor injection, sterile water for irrigation, purified water); Sorbents(powdered cellulose, charcoal, purified siliceous earth); carbon dioxidesorbents (barium hydroxide lime, soda lime); stiffening agents(hydrogenated castor oil, cetostearyl alcohol, cetyl alcohol, cetylesters wax, hard fat, paraffin, polyethylene excipient, stearyl alcohol,emulsifying wax, white wax, yellow wax); Suspending and/orviscosity-increasing agents (acacia, agar, alginic acid, aluminummonostearate, bentonite, purified bentonite, magma bentonite, carbomer,carboxymethylcellulose calcium, carboxymethylcellulose sodium,carboxymethylcellulose sodium 12, carrageenan, microcrystalline andcarboxymethylcellulose sodium cellulose, dextrin, gelatin, guar gum,hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, magnesium aluminum silicate, methylcellulose, pectin,polyethylene oxide, polyvinyl alcohol, povidone, alginate, silicondioxide, colloidal silicon dioxide, sodium alginate, tragacanth, xanthangum); sweetening agents (aspartame, dextrates, dextrose, excipientdextrose, fructose, mannitol, saccharin, calcium saccharin, sodiumsaccharin, sorbitol, solution sorbitol, sucrose, compressible sugar,confectioner's sugar, syrup); tablet binders (acacia, alginic acid,sodium carboxymethylcellulose, microcrystalline cellulose, dextrin,ethylcellulose, gelatin, liquid glucose, guar gum, hydroxypropylmethylcellulose, methylcellulose, polyethylene oxide, povidone,pregelatinized starch, syrup); tablet and/or capsule diluents (calciumcarbonate, dibasic calcium phosphate, tribasic calcium phosphate,calcium sulfate, microcrystalline cellulose, powdered cellulose,dextrates, dextrin, dextrose excipient, fructose, kaolin, lactose,mannitol, sorbitol, starch, pregelatinized starch, sucrose, compressiblesugar, confectioner's sugar); tablet disintegrants (alginic acid,microcrystalline cellulose, croscarmellose sodium, crospovidone,polacrilin potassium, sodium starch glycolate, starch, pregelatinizedstarch); Tablet and/or capsule lubricants (calcium stearate, glycerylbehenate, magnesium stearate, light mineral oil, sodium stearylfumarate, stearic acid, purified stearic acid, talc, hydrogenatedvegetable oil, zinc stearate); tonicity agent (dextrose, glycerol,mannitol, potassium chloride, sodium chloride); vehicle: flavored and/orsweetened (aromatic elixir, compound benzaldehyde elixir, iso-alcoholicelixir, peppermint water, sorbitol solution, syrup, tolu balsam syrup);vehicle: oleaginous (almond oil, corn oil, cottonseed oil, ethyl oleate,isopropyl myristate, isopropyl palmitate, mineral oil, light mineraloil, myristyl alcohol, octyldodecanol, olive oil, peanut oil, persicoil, sesame oil, soybean oil, squalane); vehicle: solid carrier (sugarspheres); vehicle: sterile (bacteriostatic water for injection,bacteriostatic sodium chloride injection); viscosity-increasing (seesuspending agent); water repelling agent (cyclomethicone, dimethicone,simethicone); and/or solubilizing agent (benzalkonium chloride,benzethonium chloride, cetylpyridinium chloride, docusate sodium,nonoxynol 9, nonoxynol 10, octoxynol 9, poloxamer, polyoxyl 35 castoroil, polyoxyl 40, hydrogenated castor oil, polyoxyl 50 stearate,polyoxyl 10 oleyl ether, polyoxyl 20, cetostearyl ether, polyoxyl 40stearate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate80, sodium lauryl sulfate, sorbitan monolaurate, sorbitan monooleate,sorbitan monopalmitate, sorbitan monostearate, tyloxapol). This list isnot meant to be exclusive, but instead merely representative of theclasses of excipients and the particular excipients that may be used inoral dosage forms as described herein.

One embodiment described herein, is a pharmaceutical compositioncomprising any of the formulations shown in the Tables or Examplesdescribed herein. Any of the components of the formulations shown in theTables or Examples can be increased, decreased, combined, recombined,switched, or removed to provide for a formulation comprising about 100%by weight.

Another embodiment described herein is a method for preparing abusedeterrent pharmaceutical compositions comprising the abuse deterrentcontrolled release matrix described herein comprising (a) mixing one ormore optional viscosity modifiers, one or more release modifiers, andone or more antioxidants in one or more flowability enhancers to form afirst mixture; (b) adding one or more active pharmaceutical ingredientto the first mixture to form a matrix fill mixture; (c) filling thematrix fill mixture into capsule shells using standard rotary dieencapsulation techniques; and (d) annealing the capsules at an elevatedtemperature for a period of time. In one aspect, the flowabilityenhancer is heated to a first elevated temperature prior to mixing theviscosity modifier and/or release modifiers. In another aspect, theflowability enhancer or mixture comprising the flowability enhancer iscooled to a second temperature. In another aspect, the flowabilityenhancer or mixture comprising the flowability enhancer is cooled to athird temperature. In another aspect, the one or more viscositymodifiers are added to the heated flowability enhancer before adding theone or more release modifiers. In another aspect, the heated mixture iscooled to a second elevated temperature prior to adding the activepharmaceutical ingredient and the one or more release modifiers. Inanother aspect, the active pharmaceutical ingredient is added prior toadding the one or more release modifiers. In another aspect, one or moreantioxidants are added prior to adding the one or more releasemodifiers. In another aspect, a first viscosity modifier is added to theflowability enhancer at a first temperature, followed by cooling themixture to a second temperature and adding one or more antioxidants tothe mixture, and cooling the mixture to a third temperature and addingthe active pharmaceutical ingredient and release modifier.

In another embodiment, the method for preparing the abuse deterrentpharmaceutical compositions described herein comprise (a) heating one ormore flowability enhancers to a first temperature; (b) adding one ormore antioxidants and mixing; (c) adding one or more release modifiersto the mixture of b; (d) cooling the mixture to a second temperature;(e) adding one or more active pharmaceutical ingredients to the cooledmixture of step d; (f) deaerating the mixture of step e; (g) filling thedeaerated mixture of step f into capsule shells using rotary dieencapsulation techniques; (h) annealing the capsules at an elevatedtemperature for a period of time; and (i) slowly cooling the annealedcapsules of h to room temperature in a controlled manner. In one aspect,the elevated annealing temperature of step h is from about 60° C. toabout 80° C. and the period of time is from about 30 min to about 120min. In one aspect, the controlled cooling of step i comprises coolingthe capsules at a rate of about 5° C. per about 10 to about 15 min.

In another embodiment, the method for preparing the abuse deterrentpharmaceutical compositions described herein comprise (a) heating one ormore flowability enhancers to a first temperature; (b) adding one ormore viscosity modifiers to the heated flowability enhancer and mixing;(c) cooling the mixture of step b to a second temperature; (d) addingone or more antioxidants to the mixture of step c and mixing; (e)cooling the mixture of step d to a third temperature; (f) adding one ormore release modifiers and the active pharmaceutical ingredient to thecooled mixture of step e and mixing; (g) filling the matrix fill mixtureinto capsule shells using standard rotary die encapsulation techniques;(h) annealing the capsules at an elevated temperature for a period oftime; and (i) cooling the capsules to room temperature in a controlledmanner. In one aspect, the elevated annealing temperature of step h isfrom about 60° C. to about 80° C. and the period of time is from about30 min to about 120 min. In one aspect, the controlled cooling comprisescooling the capsules at a rate of about 5° C. per about 10 to about 15min.

Another embodiment described herein is a method for manufacturing anabuse deterrent pharmaceutical composition comprising (a) heating one ormore flowability enhancers to about 55° C. to about 70° C. undernitrogen; (b) adding one or more antioxidants to the flowabilityenhancer and mixing at about 50 to about 300 RPM until dissolved; (c)cooling the mixture of step b to about 25° C. to about 35° C. whilemixing at about 50 to about 300 RPM; (d) adding the activepharmaceutical ingredient and mixing at about 50 to about 300 RPM forabout 30 min; (e) adding a viscosity modifier to the mixture of step dand mixing at about 50 to about 300 RPM for about 30 min; (f) deaeratingthe mixture of step e for at least about 30 min; (g) maintaining thedeaerated mixture at a third temperature with continuous mixing at about50 to about 100 RPM under nitrogen during encapsulation; (h)encapsulating the mixture of step g into soft capsule shells usingrotary die encapsulation; (i) drying the capsules; (i) removingprocessing lubrication with isopropyl alcohol; (j) transferring thecapsules to a coating pan operating at about 1-2 RPM at a temperature ofabout 30° C. to about 35° C.; (k) coating the capsules of step j with acoating composition at about 1-2 RPM until about 10% to about 20% weightgain is achieved; (1) heating the capsules of step k to about 60° C. toabout 80° C. for about 30 min to about 90 min at about 1-2 RPM; (m)cooling the capsules of step/to about 30° C. at a rate of about 2° C. toabout 10° C. per each about 5 min to about 20 min period whilemaintaining about 1-2 RPM; (n) cooling the capsules of step m from about30° C. to room temperature (ca. 25° C.) while maintaining about 1-2 RPM;(o) printing labels on the capsule; and (p) packaging the capsules. Inone aspect described herein, the coating and annealing process areconducted in a coating pan.

In one embodiment, the methods for preparing the abuse deterrentpharmaceutical compositions described herein comprise heating theflowability enhancer or a mixture comprising the flowability enhancer toa first temperature. In one aspect, the first temperature is about 40°C. to about 170° C., including each integer within the specified range.In another aspect, the first temperature is about 120° C. to about 170°C., including each integer within the specified range. In anotheraspect, the first temperature is about 40° C. to about 90° C., includingeach integer within the specified range. In another aspect, the firsttemperature is about 40° C. to about 90° C., including each integerwithin the specified range. In another aspect, the first temperature isabout 40° C., about 45° C., about 50° C., about 55° C., about 60° C.,about 65° C., about 70° C., about 75° C., about 80° C., about 90° C.,about 100° C., about 110° C., about 120° C., about 130° C., about 140°C., about 150° C., about 160° C., or about 170° C.

In another embodiment, the methods for preparing the abuse deterrentpharmaceutical compositions described herein comprise cooling theflowability enhancer or a mixture comprising the flowability enhancer toa second temperature. In one aspect, the second temperature is about 25°C. to about 100° C., including each integer within the specified range.In another aspect, the second temperature is about 25° C. to about 50°C., including each integer within the specified range. In anotheraspect, the second temperature is about 40° C. to about 90° C.,including each integer within the specified range. In another aspect,the second temperature is about 40° C. to about 90° C., including eachinteger within the specified range. In another aspect, the secondtemperature is about 25° C., about 30° C., about 35° C., about 40° C.,about 45° C., about 50° C., about 55° C., about 60° C., about 65° C.,about 70° C., about 75° C., about 80° C., about 90° C., or about 100° C.

In another embodiment, the methods for preparing the abuse deterrentpharmaceutical compositions described herein comprise cooling theflowability enhancer or a mixture comprising the flowability enhancer toa third temperature. In one aspect, the third temperature is about 25°C. to about 100° C., including each integer within the specified range.In another aspect, the third temperature is about 25° C. to about 50°C., including each integer within the specified range. In anotheraspect, the third temperature is about 40° C. to about 90° C., includingeach integer within the specified range. In another aspect, the thirdtemperature is about 40° C. to about 90° C., including each integerwithin the specified range. In another aspect, the third temperature isabout 25° C., about 30° C., about 35° C., about 40° C., about 45° C.,about 50° C., about 55° C., about 60° C., about 65° C., about 70° C.,about 75° C., about 80° C., about 90° C., or about 100° C.

In another embodiment, the methods for preparing the abuse deterrentpharmaceutical compositions described herein comprise annealing thepharmaceutical composition comprising a soft or capsule shell and amatrix fill as described herein at specified temperature for a period oftime. In one aspect, the temperature ranges from about 45° C. to about120° C., including each integer within the specified range. In anotheraspect, the temperature ranges from about 55° C. to about 85° C.,including each integer within the specified range. In another aspect,the temperature is about 45° C., about 50° C., about 55° C., about 60°C., about 65° C., about 70° C., about 75° C., about 80° C., about 90°C., about 100° C., about 110° C., or about 120° C. In another aspect,the annealing time ranges from about 10 minutes to about 160 minutes,including each integer within the specified range. In another aspect,the annealing time ranges from about 1 minute to about 80 minutes,including each integer within the specified range. In another aspect,the annealing time ranges from about 40 minutes to about 80 minutes,including each integer within the specified range. In another aspect,the annealing time is about 1 min, about 3 min, about 6 min, about 9min, about 12 min, about 15 min, about 20 min, about 25 min, about 30min, about 35 min, about 40 min, about 45 min, about 50 min, about 55min, about 60 min, about 70 min, about 80 min, about 90 min, about 100min, about 110 min, about 120 min, about 130 min, about 140 min, about150 min, or about 160 min.

In another embodiment, the abuse deterrent pharmaceutical compositiondescribed herein provides a dosage of an active pharmaceuticalingredient described herein for administration to a subject. The dosageform can be administered, for example, to a subject, or a subject inneed thereof. In one aspect, the subject is a mammal, or a mammal inneed thereof. In one aspect, the subject is a human, or human in needthereof. In one aspect, the human or human in need thereof is a medicalpatient. In one aspect, the human subject is a child (˜0-9 years old) oran adolescent (˜10-17 years old). In one aspect, the subject is from 0to 9 years of age. In another aspect, the human subject is from 10 to 17years of age. In another aspect, the human subject is over 17 years ofage. In another aspect, the human subject is an adult (>18 years ofage).

In one embodiment, the dosage may be administered to a human in need ofmanagement of moderate to severe chronic pain and neuropathic painassociated with diabetic peripheral neuropathy (DPN), when a continuous,persistent (around-the-clock) opioid analgesic is needed for an extendedperiod of time.

The dosage form can be administered, for example, 1×, 2×, 3×, 4×, 5×,6×, or even more times per day. One or more dosage form can beadministered, for example, for 1, 2, 3, 4, 5, 6, 7 days, or even longer.One or more dosage forms can be administered, for example, for 1, 2, 3,4 weeks, or even longer. One or more dosage forms can be administered,for example, for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months, 1 year,2, years, 3 years, 4 years, 5 years, over 5 years, a decade, multipledecades, or even longer. One or more dosage forms can be administered ata regular interval until the subject or subject in need thereof, doesnot require treatment, prophylaxis, or amelioration of any disease orcondition, including but not limited to, pain.

In one embodiment, the pharmaceutical composition described herein isadministered in multiple dosages simultaneously to achieve a desireddose. For example, two or more identical dosages are administered at onetime to achieve a desired dose. Two 40 mg dosage forms may beadministered simultaneously to provide 80 mg. Likewise, three 40 mgdosage forms or four 30 mg dosage forms may be administeredsimultaneously to provide 120 mg. In another embodiment, two or moredifferent dosages are administered at one time. Such dual or differentsimultaneous doses can be used to provide an effective dose of thepharmaceutical composition to a subject in need thereof.

In one embodiment, the abuse deterrent oral composition describedherein, comprises one or more active pharmaceutical ingredients in anamount of about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg,about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, about 280mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355mg, about 360 mg, about 365 mg, about 370 mg, about 375 mg, about 380mg, about 385 mg, about 390 mg, about 395 mg, about 400 mg, about 405mg, about 410 mg, about 415 mg, about 420 mg, about 425 mg, about 430mg, about 435 mg, about 440 mg, about 445 mg, about 450 mg, about 455mg, about 460 mg, about 465 mg, about 470 mg, about 475 mg, about 480mg, about 485 mg, about 490 mg, about 495 mg, about 500 mg, or evenmore.

In another embodiment, the abuse deterrent oral composition describedherein, comprises one or more active pharmaceutical ingredients in therange of about 20 mg to about 250 mg, about 30 mg to about 250 mg, about40 mg to about 250 mg, about 50 mg to about 250 mg, about 60 mg to about250 mg, about 70 mg to about 250 mg, about 80 mg to about 250 mg, about90 mg to about 250 mg, about 100 mg to about 250 mg, about 110 mg toabout 250 mg, about 120 mg to about 250 mg, about 130 mg to about 250mg, about 140 mg to about 250 mg, about 150 mg to about 250 mg, about160 mg to about 250 mg, about 170 mg to about 250 mg, about 180 mg toabout 250 mg, about 190 mg to about 250 mg, about 200 mg to about 250mg, about 210 mg to about 250 mg, about 220 mg to about 250 mg, about230 mg to about 250 mg, about 240 mg to about 250 mg; about 250 mg toabout 500 mg, about 260 mg to about 500 mg, about 270 mg to about 500mg, about 280 mg to about 500 mg, about 290 mg to about 500 mg, about300 mg to about 500 mg, about 310 mg to about 500 mg, about 320 mg toabout 500 mg, about 330 mg to about 500 mg, about 340 mg to about 500mg, about 350 mg to about 500 mg, about 360 mg to about 500 mg, about370 mg to about 500 mg, about 380 mg to about 500 mg, about 390 mg toabout 500 mg, about 400 mg to about 500 mg, about 410 mg to about 500mg, about 420 mg to about 500 mg, about 430 mg to about 500 mg, about440 mg to about 500 mg, about 450 mg to about 500 mg, about 460 mg toabout 500 mg, about 470 mg to about 500 mg, about 480 mg to about 500mg, or about 490 mg to about 500 mg.

In one embodiment described herein, the abuse deterrent oral compositiondescribed herein may comprise an active pharmaceutical ingredient load(e.g., a drug load of one or more active pharmaceutical ingredients) ofabout 1% to about 90%, including each integer within the specifiedrange. In one embodiment, the drug load can comprise about 1%, about 2%,about 2.5%, about 5%, about 10%, about 15%, about 20%, about 25%, about30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%,about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, oreven higher. In one aspect, the drug load is about 3%. In one aspect,the drug load is about 5%. In one aspect, the drug load is about 6%. Inone aspect, the drug load is about 9%. In one aspect, the drug load isabout 10%. In one aspect, the drug load is about 12%. In one aspect, thedrug load is about 15%. In one aspect, the drug load is about 20%. Inone aspect, the drug load is about 25%. In one aspect, the drug load isabout 30%. In one aspect, the drug load is about 35%. In one aspect, thedrug load is about 40%. In one aspect, the drug load is about 50%. Inone aspect, the drug load is about 60%. In one aspect, the drug load isabout 28%. In one aspect, the drug load is about 32%. In one aspect, thedrug load is about 44%. In one embodiment, the drug load is about 48%.

In one embodiment, the active pharmaceutical ingredient is oxycodone,hydrocodone or codeine, or a salt, ether, ester, variant, or derivativethereof. In one embodiment, the active pharmaceutical ingredient isoxycodone. In one embodiment, the active pharmaceutical ingredient isoxycodone hydrochloride. In another embodiment, the activepharmaceutical ingredient is hydrocodone. See Prescribing Informationfor OxyContin® ER 04/2014 (Purdue Pharma LP; available atwww.purduepharma.com) and Zohydro® ER 01/2015 (Zogenix® Inc.; availableat: www.zogenix.com), which are incorporated by reference herein forsuch teachings.

In another embodiment, the active pharmaceutical ingredient may compriseoxycodone, hydrocodone, or codeine and an additional activepharmaceutical ingredient. In one aspect, the additional activepharmaceutical ingredient prevents opioid abuse when an excess of opioidis used. In another aspect, the additional active pharmaceuticalingredient reduces or prevents opioid induced side effects.

In one embodiment, the active pharmaceutical ingredient comprisesoxycodone hydrochoride. The oxycodone may comprise trace amounts ofimpurities from the manufacturing process. In one embodiment describedherein, the oxycodone hydrochloride comprises greater than 25 ppm of14-hydroxycodeinone, but less than 100 ppm. In another embodiment theoxycodone hydrochloride comprises about 50 ppm of 14-hydroxycodeinone.In another embodiment the oxycodone hydrochloride comprises about 90 ppmof 14-hydroxycodeinone. In another embodiment the oxycodonehydrochloride comprises <100 ppm of 14-hydroxycodeinone.

In one embodiment, the abuse deterrent oral composition described hereincomprises a dose of opioid analgesic. In one aspect, the dose of opioidanalgesic is about 5 mg. In one aspect, the dose of opioid analgesic isabout 10 mg. In one aspect, the dose of opioid analgesic is about 20 mg.In another aspect, the dose of opioid analgesic is about 30 mg. Inanother aspect, the dose of opioid analgesic is about 40 mg. In anotheraspect, the dose of opioid analgesic is about 50 mg. In another aspect,the dose of opioid analgesic is about 60 mg. In another aspect, the doseof opioid analgesic is about 70 mg. In another aspect, the dose ofopioid analgesic is about 80 mg. In another aspect, the dose of opioidanalgesic is about 90 mg. In another aspect, the dose of opioidanalgesic is about 100 mg. In another aspect, the dose of opioidanalgesic is about 120 mg. In another aspect, the dose of opioidanalgesic is about 140 mg. In another aspect, the dose of opioidanalgesic is about 160 mg. In another aspect, the dose of opioidanalgesic is about 180 mg. In another aspect, the dose of opioidanalgesic is about 200 mg.

In one embodiment, the abuse deterrent oral composition described hereincomprises a dose of oxycodone. In one aspect, the dose of oxycodone isabout 5 mg. In another aspect, the dose of oxycodone is about 10 mg. Inanother aspect, the dose of oxycodone is about 15 mg. In another aspect,the dose of oxycodone is about 20 mg. In another aspect, the dose ofoxycodone is about 30 mg. In another aspect, the dose of oxycodone isabout 40 mg. In another aspect, the dose of oxycodone is about 50 mg. Inanother aspect, the dose of oxycodone is about 60 mg. In another aspect,the dose of oxycodone is about 70 mg. In another aspect, the dose ofoxycodone is about 80 mg. In another aspect, the dose of oxycodone isabout 100 mg. In another aspect, the dose of oxycodone is about 120 mg.In another aspect, the dose of oxycodone is about 140 mg. In anotheraspect, the dose of oxycodone is about 160 mg. In another aspect, thedose of oxycodone is about 180 mg. In another aspect, the dose ofoxycodone is about 200 mg.

In another embodiment, the total dosage of oxycodone administered in a24-hour period is about 20 mg to about 600 mg per 24-hour period. In oneaspect, the total dosage of oxycodone or hydrocodone administered in a24-hour period is about 50 mg to about 250 mg per 24-hour period. Thedosage can contain a total amount of oxycodone effective for treatment,amelioration, prophylaxis, or reducing the onset of or symptoms of pain.

In one embodiment, the recommended dosage is based upon the condition ofthe subject in need thereof. The subject can comprise a human or mammalin need thereof. In one aspect, the need is defined as a painfulcondition or perception of pain. In one embodiment, the perception ofpain is described as a numerical scale. In one aspect, this numericalscale indicates 0 for no pain, 1-3 suggestive of mild pain; annoying ornagging pain that does not affect the activities of daily life, 4-6 formoderate pain that interferes significantly with the activities of dailylife, and 7-10 for severe pain that is disabling for which theactivities of daily life are not possible. Another aspect describedherein comprises orally administering a maximal dosage of about 10 mg toabout 120 mg of oxycodone every 24 hours for humans or mammals with apain of 1-3. Another aspect described herein comprises orallyadministering a maximal dosage of about 80 mg to about 400 mg ofoxycodone every 24 hours for humans or mammals with a pain of 4-6.Another aspect described herein comprises orally administering a maximaldosage of 120 mg to about 600 mg of oxycodone every 24 hours for humansor mammals with a pain of 7-10. In one aspect, the level of pain isassessed by observing the human or mammal.

Another aspect described herein comprises orally administering a delayedrelease dosage of about 10 mg of oxycodone every 12 hours for a human ormammal with a pain of 1-3. Another aspect described herein comprisesorally administering a delayed release dosage of about 30 mg ofoxycodone 1 every 12 hours for a human or mammal with a pain of 4-6.Another aspect described herein comprises orally administering a delayedrelease dosage of about 80 mg of oxycodone every 12 hours for a human ormammal with a pain of 7-10. Another aspect described herein comprisesincreasing the delayed release dosage of oxycodone by 10 mg incrementsevery 24 hours to a maximal daily dosage of 600 mg if pain of any typeis not ameliorated in the human or mammal in need thereof. Anotheraspect described herein comprises decreasing the dosage of oxycodone asneeded every 24 hours if pain of any type has decreased or has beenameliorated in the human or mammal in need thereof.

In one embodiment, the recommended dosage is based upon the condition ofthe subject in need thereof. The subject can comprise a human or mammalin need thereof. In one aspect, the need is defined as a painfulcondition or perception of pain. In one embodiment, the initial dosageof opioid analgesic is 10 mg to about 40 mg. In one aspect, an initialdose of about 10 mg to about 40 mg is suitable for a subject that nottolerant of an opioid. In one aspect, the initial dose is about 10 mg ofopioid analgesic. In another aspect, the initial dose is about 20 mg ofopioid analgesic. In another aspect, the initial dose is about 20 mg ofopioid analgesic. In another aspect, the initial dose is about 30 mg ofopioid analgesic. In another aspect, the initial dose is about 40 mg ofopioid analgesic. In another aspect, the dose of opioid analgesic may bemaintained and given every 8 to 12 hours. In another aspect, the dose ofopioid analgesic may be increased by about 10 mg to about 20 mg every 8hrs to 12 hrs until pain relief occurs.

In another embodiment, the initial dosage of opioid analgesic is 40 mgto about 80 mg. In one aspect, an initial dose of about 40 mg to about80 mg is suitable for a subject that has an opioid tolerant phenotype.In one aspect, the initial dose is about 40 mg of opioid analgesic. Inanother aspect, the initial dose is about 50 mg of opioid analgesic. Inanother aspect, the initial dose is about 60 mg of opioid analgesic. Inanother aspect, the initial dose is about 70 mg of opioid analgesic. Inanother aspect, the initial dose is about 80 mg of opioid analgesic. Inanother aspect, the dose of opioid analgesic may be maintained and givenevery 8 to 12 hours. In another aspect, the dose of opioid analgesic maybe increased by about 10 mg to about 20 mg every 8 hrs to 12 hrs untilpain relief occurs.

In one embodiment, the recommended dosage is based upon the condition ofthe subject in need thereof. The subject can comprise a human or mammalin need thereof. In one aspect, the need is defined as a painfulcondition or perception of pain. In one embodiment, the initial dosageof oxycodone is 10 mg to about 40 mg. In one aspect, an initial dose ofabout 10 mg to about 40 mg is suitable for a subject that not tolerantof an opioid and a dose. In one aspect, the initial dose is about 10 mgof oxycodone. In another aspect, the initial dose is about 20 mg ofoxycodone. In another aspect, the initial dose is about 20 mg ofoxycodone. In another aspect, the initial dose is about 30 mg ofoxycodone. In another aspect, the initial dose is about 40 mg ofoxycodone. In another aspect, the dose of oxycodone may be maintainedand given every 8 to 12 hours. In another aspect, the dose of oxycodonemay be increased by about 10 mg to about 20 mg every 8 hrs to 12 hrsuntil pain relief occurs.

In another embodiment, the initial dosage of oxycodone is 40 mg to about160 mg. In one aspect, an initial dose of about 40 mg to about 80 mg issuitable for a subject that has an opioid tolerant phenotype. In oneaspect, the initial dose is about 40 mg of oxycodone. In another aspect,the initial dose is about 50 mg of oxycodone. In another aspect, theinitial dose is about 60 mg of oxycodone. In another aspect, the initialdose is about 70 mg of oxycodone. In another aspect, the initial dose isabout 80 mg of oxycodone. In another aspect, the initial dose is about100 mg of oxycodone. In another aspect, the initial dose is about 120 mgof oxycodone. In another aspect, the initial dose is about 140 mg ofoxycodone. In another aspect, the initial dose is about 160 mg ofoxycodone. In another aspect, the dose of oxycodone may be maintainedand given every 8 to 12 hours. In another aspect, the dose of oxycodonemay be increased by about 10 mg to about 20 mg every 8 hrs to 12 hrsuntil pain relief occurs.

Additionally, the abuse deterrent pharmaceutical compositions describedherein may be useful for the treatment of pain stemming from, includingbut not limited to, chronic arthritis, osteoarthritis, rheumatoidarthritis, acute tendonitis, bursitis, headaches, migraines, chronicneuropathies, shingles, premenstrual symptoms, sports injuries,malignancy, radiculopathy, sciatica/sciatic pain, sarcoidosis,necrobiosis, lipoidica, trauma, or granuloma annulare.

Another embodiment described herein is an abuse deterrent pharmaceuticalcomposition as described herein for administration to a subject havingpain, comprising a therapeutically effective amount of one or moreactive pharmaceutical ingredients, wherein the subject achieves areduction of pain relative to baseline without substantiallyexperiencing one or more side effects including, but not limited to,headache, vertigo, somnolence, nausea, constipation, vomiting,xerostomia, fatigue, pruritus, eructation, heartburn, abdominaldiscomfort, or loss of appetite.

Another embodiment described herein is an abuse deterrent pharmaceuticalcomposition as described herein for administration to a subject havingpain, comprising a therapeutically effective amount of one or moreactive pharmaceutical ingredients exhibiting an in vitro dissolutionrate at pH 1.2 comprising about 35% to about 95% dissolution after about60 minutes to about 480 minutes including each integer within thespecified ranges of dissolution and time. In one aspect, the in vitrodissolution rate at pH 1.2 is about 35% after about 60 min, about 50%after about 120 min, about 70% after about 240 min, about 85% afterabout 480 min.

Another embodiment described herein is an abuse deterrent pharmaceuticalcomposition as described herein for administration to a subject havingpain, comprising a therapeutically effective amount of one or moreactive pharmaceutical ingredients exhibiting an in vitro dissolutionrate at pH 1.2 comprising about 15% to about 95% dissolution after about60 minutes to about 480 minutes including each integer within thespecified ranges of dissolution and time. In one aspect, the in vitrodissolution rate at pH 1.2 is about 10% after about 60 min, about 20%after about 90 minutes, about 50% after about 120 min, about 70% afterabout 240 min, about 85% after about 480 min.

In another embodiment, the abuse deterrent pharmaceutical compositioncomprising an abuse deterrent matrix as described herein reduces thedissolution and extraction of an active pharmaceutical ingredient.Suitable non-limiting examples of extraction methods comprise incubatingthe abuse deterrent pharmaceutical composition in boiling conditions, inaqueous solutions of alcohol, and in distilled water. These methods maybe used in conjunction with additional means of agitating, for example,with paddles, dipping, vigourous shaking, physical manipulations, andthe like.

In another embodiment, the abuse deterrent pharmaceutical composition asdescribed herein has an in vitro dissolution rate under boilingconditions in an aqueous media (e.g., a temperature of about 90° C. toabout 120° C.) is less than about 35% to about 60% after about 10minutes to about 45 minutes, including each integer within the specifiedranges of dissolution and time. In one aspect, the in vitro dissolutionrate of the controlled release pharmaceutical composition under boilingconditions in an aqueous media is less than about 50% after about 5minutes. In another aspect, the in vitro dissolution rate of thecontrolled release pharmaceutical composition under boiling conditionsin an aqueous media is less than about 50% after about 10 minutes. Inanother aspect, the in vitro dissolution rate of the controlled releasepharmaceutical composition under boiling conditions in an aqueous mediais less than about 50% after about 20 minutes. In another aspect, the invitro dissolution rate of the controlled release pharmaceuticalcomposition under boiling conditions in an aqueous media is less thanabout 50% after about 30 minutes. In another aspect, the in vitrodissolution rate of the controlled release pharmaceutical compositionunder boiling conditions in an aqueous media is less than about 60%after about 45 minutes.

In another embodiment, the abuse deterrent controlled releasepharmaceutical composition as described herein has an in vitrodissolution rate in an aqueous alcohol solution (e.g., an aqueoussolution of ethanol of 80%) of less than about 20% to about 50% afterabout 30 minutes to about 360 minutes, including each integer within thespecified ranges of dissolution and time. In one aspect, the in vitrodissolution rate of the controlled release pharmaceutical composition inan aqueous alcohol solution is less than about 10% after about 30minutes. In another aspect, the in vitro dissolution rate of thecontrolled release pharmaceutical composition in an aqueous alcoholsolution is less than about 20% after about 60 minutes. In anotheraspect, the in vitro dissolution rate of the controlled releasepharmaceutical composition in an aqueous alcohol solution is less thanabout 50% after about 60 minutes. In another aspect, the in vitrodissolution rate of the controlled release pharmaceutical composition inan aqueous alcohol solution is less than about 50% after about 120minutes. In another aspect, the in vitro dissolution rate of thecontrolled release pharmaceutical composition in an aqueous alcoholsolution is less than about 50% after about 180 minutes. In anotheraspect, the in vitro dissolution rate of the controlled releasepharmaceutical composition in an aqueous alcohol solution is less thanabout 50% after about 360 minutes.

Another embodiment described herein is an abuse deterrent pharmaceuticalcomposition as described herein comprising a therapeutically effectiveamount of one or more active pharmaceutical ingredients foradministration to a subject having pain, exhibiting an in vitrodissolution rate at pH 1.2 of about 35% to about 95% after about 60minutes to about 480 minutes, an in vitro dissolution rate under boilingconditions less than about 35% to about 60% after about 10 minutes toabout 45 minutes, and an in vitro dissolution rate in an aqueous alcoholsolution of less than about 20% to about 50% after about 30 minutes toabout 360 minutes.

Another embodiment described herein is an abuse deterrent pharmaceuticalcomposition as described herein comprising a therapeutically effectiveamount of one or more active pharmaceutical ingredients foradministration to a subject having pain, exhibiting an in vitrodissolution rate as described herein in any one of Drawings 1-7, 9,11-22, or 28.

Another embodiment described herein is a method for orally administeringa dosage form of an abuse deterrent pharmaceutical compositioncomprising an active pharmaceutical ingredient described herein for thetreatment, amelioration, prophylaxis, or reducing the onset of orsymptoms of pain.

Another embodiment described herein is a method for treating, retardingthe progression of, delaying the onset of, prophylaxis of, ameliorationof, or reducing the symptoms of pain, comprising administering to asubject in need thereof an oral pharmaceutical composition as describedherein comprising a therapeutically effective amount of one or moreactive pharmaceutical ingredients for administration to a subject havingpain, wherein the pharmaceutical composition exhibits an in vitrodissolution rate at pH 1.2, of about 35% to about 95% after about 60minutes to about 480 minutes, an in vitro dissolution rate under boilingconditions less than about 35% to about 60% after about 10 minutes toabout 45 minutes, and an in vitro dissolution rate in an aqueous alcoholsolution of less than about 20% to about 50% after about 30 minutes toabout 360 minutes.

Another embodiment described herein is a method for treating, retardingthe progression of, delaying the onset of, prophylaxis of, ameliorationof, or reducing the symptoms of pain, comprising administering to asubject in need thereof an oral pharmaceutical composition as describedherein comprising a therapeutically effective amount of one or moreactive pharmaceutical ingredients for administration to a subject havingpain, exhibiting an in vitro dissolution rate as described herein in anyone of Drawings 1-7, 9, 11-22, or 28.

Another embodiment described herein is a method for treating anindividual having pain, with a pharmaceutical composition describedherein comprising an abuse deterrent matrix described herein comprisinga dosage of about 10 mg of oxycodone to about 80 mg of oxycodone,wherein subjects administered a single dosage exhibit a mean plasmaoxycodone C_(max) of about 10 ng/mL to about 150 ng/mL, including eachinteger within the specified range. In one aspect, the composition isprovided in a dosage form containing a total amount of about 10 mg ofoxycodone, wherein subjects administered a single dosage exhibit a meanplasma oxycodone C_(max) of about 10 ng/mL. In another aspect, thecomposition is provided in a dosage form containing a total amount ofabout 20 mg of oxycodone, wherein subjects administered a single dosageexhibit a mean plasma oxycodone C_(max) of about 20 ng/mL. In anotheraspect, the composition is provided in a dosage form containing a totalamount of about 40 mg of oxycodone, wherein subjects administered asingle dosage exhibit a mean plasma oxycodone C_(max) of about 40 ng/mL.In another aspect, the composition is provided in a dosage formcontaining a total amount of about 80 mg of oxycodone, wherein subjectsadministered a single dosage exhibit a mean plasma oxycodone C_(max) ofabout 100 ng/mL.

Another embodiment described herein is a method for treating anindividual having pain, with a pharmaceutical composition describedherein comprising an abuse deterrent matrix described herein comprisinga dosage of about 10 mg of oxycodone to about 80 mg of oxycodone,wherein subjects administered a single dosage exhibit a mean plasmaoxycodone AUC_(0→∞) of about 100 h·mg/L to about 1000 h·mg/L, includingeach integer within the specified range. In one aspect, the compositionis provided in a dosage form containing a total amount of about 10 mg ofan oxycodone, wherein subjects administered a single dosage exhibit amean plasma oxycodone AUC_(0→∞) of about 100 h·mg/L. In another aspect,the composition is provided in a dosage form containing a total amountof about 20 mg of oxycodone, wherein subjects administered a singledosage exhibit a mean plasma oxycodone AUC_(0→∞) of about 200 h·mg/L. Inanother aspect, the composition is provided in a dosage form containinga total amount of about 40 mg of oxycodone, wherein subjectsadministered a single dosage exhibit a mean plasma oxycodone AUC_(0→∞)of about 400 h·mg/L. In another aspect, the composition is provided in adosage form containing a total amount of about 80 mg of oxycodone,wherein subjects administered a single dosage exhibit a mean plasmaoxycodone AUC_(0→∞) of about 1000 h·mg/L.

Another embodiment described herein is a method for treating anindividual having pain, with a pharmaceutical composition describedherein comprising an abuse deterrent matrix described herein comprisinga dosage of about 10 mg of oxycodone to about 80 mg of oxycodone,wherein subjects administered a single dosage exhibits a T_(max) ofabout 1 hr to about 8 hrs, including each integer within the specifiedrange. In one aspect, the composition is provided in a dosage formcontaining a total amount of about 10 mg to about 80 mg of oxycodone,wherein subjects administered a single dosage exhibit a T_(max) of about1 hr, about 1.5 hrs, about 2 hrs, about 2.5 hrs, about 3 hrs, about 3.5hrs, about 4 hrs, 4.5 hrs, 5 hrs, 5.5 hrs, 6 hrs, 6.5 hrs, 7 hrs, 7.5hrs, or about 8 hrs.

Another embodiment described herein is a method for treating anindividual having pain, with a pharmaceutical composition describedherein comprising an abuse deterrent matrix described herein comprisinga dosage of about 10 mg of opioid analgesic to about 80 mg of opioidanalgesic, wherein subjects administered a single dosage exhibit a meanplasma opioid analgesic C_(max) of about 10 ng/mL to about 120 ng/mL,including each integer within the specified range. In one aspect, thecomposition is provided in a dosage form containing a total amount ofabout 10 mg of an opioid analgesic, wherein subjects administered asingle dosage exhibit a mean plasma opioid analgesic C_(max) of about 20ng/mL. In another aspect, the composition is provided in a dosage formcontaining a total amount of about 20 mg of opioid analgesic, whereinsubjects administered a single dosage exhibit a mean plasma opioidanalgesic C_(max) of about 30 ng/mL. In another aspect, the compositionis provided in a dosage form containing a total amount of about 30 mg ofopioid analgesic, wherein subjects administered a single dosage exhibita mean plasma opioid analgesic C_(max) of about 40 ng/mL. In anotheraspect, the composition is provided in a dosage form containing a totalamount of about 40 mg of opioid analgesic, wherein subjects administereda single dosage exhibit a mean plasma opioid analgesic C_(max) of about60 ng/mL. In another aspect, the composition is provided in a dosageform containing a total amount of about 80 mg of opioid analgesic,wherein subjects administered a single dosage exhibit a mean plasmaopioid analgesic C_(max) of about 120 ng/mL.

Another embodiment described herein is a method for treating anindividual having pain, with a pharmaceutical composition describedherein comprising an abuse deterrent matrix described herein comprisinga dosage of about 10 mg of opioid analgesic to about 80 mg of opioidanalgesic, wherein subjects administered a single dosage exhibit a meanplasma opioid analgesic AUC_(0→∞) of about 100 h·mg/L to about 1600h·mg/L, including each integer within the specified range. In oneaspect, the composition is provided in a dosage form containing a totalamount of about 10 mg of an opioid analgesic, wherein subjectsadministered a single dosage exhibit a mean plasma opioid analgesicAUC_(0→∞) of about 150 h·mg/L. In another aspect, the composition isprovided in a dosage form containing a total amount of about 20 mg ofopioid analgesic, wherein subjects administered a single dosage exhibita mean plasma opioid analgesic AUC_(0→∞) of about 400 h·mg/L. In anotheraspect, the composition is provided in a dosage form containing a totalamount of about 40 mg of opioid analgesic, wherein subjects administereda single dosage exhibit a mean plasma opioid analgesic AUC_(0→∞) ofabout 850 h·mg/L. In another aspect, the composition is provided in adosage form containing a total amount of about 80 mg of opioidanalgesic, wherein subjects administered a single dosage exhibit a meanplasma opioid analgesic AUC_(0→∞) of about 1600 h·mg/L.

Another embodiment described herein is a method for treating anindividual having pain, with a pharmaceutical composition describedherein comprising an abuse deterrent matrix described herein comprisinga dosage of about 10 mg of opioid analgesic to about 80 mg of opioidanalgesic, wherein subjects administered a single dosage exhibits aT_(max) of about 3 hrs to about 8 hrs, including each integer within thespecified range. In one aspect, the composition is provided in a dosageform containing a total amount of about 10 mg to about 80 mg of opioidanalgesic, wherein subjects administered a single dosage exhibit aT_(max) of about 3 hrs, about 4 hrs, about 5 hrs, about 6 hrs, about 7hrs, or about 8 hrs.

In another embodiment, the pharmaceutical compositions described hereinfurther comprise one or more active pharmaceutical ingredient(s)suitable for treating, ameliorating, or prophylactically treating abowel dysfunction due to acute or chronic opioid use, often referred toas opioid induced bowel disfunction (OIBD). Symptoms of OIBD typicallycomprise constipation (e.g., opioid induced constipation; OIC),anorexia, nausea and vomiting, gastro-oesophageal reflux, delayeddigestion, abdominal pain, flatulence, bloating, hard stools, incompleteevacuation or straining during bowel movements. Alternative oradditional uses for the one or more active pharmaceutical ingredient(s)described herein may be to treat, reduce, inhibit, or prevent additionaleffects of acute or chronic opioid use including, e.g., aberrantmigration or proliferation of endothelial cells (e.g., vascularendothelial cells), increased angiogenesis, and increase in lethalfactor production from opportunistic infectious agents (e.g.,Pseudomonas aeruginosa). Additional advantageous uses of one or moreactive pharmaceutical ingredient(s) include treatment of opioid-inducedimmune suppression, inhibition of angiogenesis, inhibition of vascularproliferation, treatment of pain, treatment of inflammatory conditionssuch as inflammatory bowel syndrome, treatment of infectious diseasesand diseases of the musculoskeletal system such as osteoporosis,arthritis, osteitis, periostitis, myopathies, and treatment ofautoimmune diseases, terminally ill patients receiving opioid therapysuch as an AIDS patient, a cancer patient, a cardiovascular patient;subjects receiving opioid therapy for maintenance of opioid withdrawal.In one aspect, the subject is a subject using an opioid for chronic painmanagement. In another aspect, the subject is a subject using an acutelyusing an opioid for temporary pain management. In another aspect, thesubject is a terminally ill patient. In another aspect, the subject is aperson receiving opioid withdrawal maintenance therapy.

In another embodiment, suitable active pharmaceutical ingredients fortreating a symptom or condition of opioid use comprise one or moreactive pharmaceutical ingredients for the treatment, amelioration, orprophylaxis of OIBD or OIC referred to herein as an anti-OIC agent. Insome aspects, the anti-OIC agent comprises a peripherally actingmu-opioid receptor antagonist (PAMORA). In some aspects, the PAMORAcomprises methylnaltrexone, naltrexone, naloxone, naloxegol,naldemadine, axelopran, or alvimopan, or a mixture or combinationthereof.

In another embodiment, suitable active pharmaceutical ingredients thatfunction as an anti-OIC agent does not function as a PAMORA. Exemplaryand non-limiting additional non-PAMORA anti-OIC agents comprise a CLC-2chloride channel agonist, such as lubiprostone; a non-selective opioidantagonist, such as levallorphan (naloxiphan), etorphine,dihydroetorphine, or diprenorphine; a mixed agonist/antagonist, such ascyclazocine, nalorphine, or nalmexone; a guanylate cyclase agonist, suchas linaclotide; or a laxative, such as docusate, magnesium citrate, orsenna.

It is understood that activation of mu-opiod receptors along the gastrointestinal tract are responsible for decreased bowel function andconstipation. Thus, without being bound by any theory, PAMORAs and otheropioid receptor antagonists described herein are useful for preventingsymptoms of OIBD, and specifically OIC, by inhibiting the action of themu-opioid receptor peripherally along the gastro-intestinal tractwithout inhibiting the mu-opiod receptors of the central nervous system(CNS). Therefore, a combination of an opioid agonist (e.g., oxycodone orother opioid analgesic) activates the CNS receptors and theco-administration of a PAMORA or other opioid antagonist inhibits theperipheral gut mu-opioid receptors, which are believed to be responsiblefor the incurrence of OIC.

It is further understood that alternative non-opioid antagonists, suchas linaclotide and lubiprostone also prevent OIC symptoms. For example,lubiprostone is known to activate the ClC-2 chloride channels. Thisactivation results in chloride-rich secretions, which soften stool andincrease bowel motility resulting in bowel movements. In addition, theguanylate cyclase agonist linaclotide is thought to activate clonicmotor neurons, which results in the promotion of bowel movements.Therefore, a combination of an opioid agonist (e.g., oxycodone or otheropioid analgesic) activates the CNS receptors and the co-administrationof a non-opioid antagonist anti-OIC agent or laxative prevents OIC bypromoting bowel movements.

In one embodiment, the pharmaceutical composition described hereincomprises a dose of an anti-OIC agent and a dose of an opioid (e.g.,oxycodone or other opioid analgesic). In one aspect, the dose of ananti-OIC agent ranges from about 50 mg to about 600 mg and the dose ofthe opioid is from about 5 mg to about 150 mg, including every integerwithin the specified ranges. In another aspect, the dose of an anti-OICagent ranges from about 50 mg to about 550 mg and the dose of the opioidis from about 5 mg to about 150 mg, including every integer within thespecified ranges. In another aspect, the dose of an anti-OIC agentranges from about 5 mg to about 50 mg and the dose of the opioid is fromabout 5 mg to about 100 mg, including every integer within the specifiedranges.

In another embodiment, the weight percentage ratio range of an anti-OICagent to opioid (e.g., oxycodone or other opioid analgesic) in thepharmaceutical composition described herein ranges from about 15:1 toabout 1:18, including each ratio within the specified range. In oneaspect, the weight percentage ratio range of an anti-OIC agent to opioidis from about 13:1 to about 1:1, including each ratio within thespecified range. In another aspect, the weight percentage ratio range ofan anti-OIC agent to opioid is from about 1:16 to about 1:1, includingeach ratio within the specified range. In another aspect, the weightpercentage ratio range of an anti-OIC agent to opioid is about 1:16,about 1:15, about 1:14, about 1:13, about 1:12, about 1:11, about 1:10,about 1:9, about 1:8, about 1:7, about 1:6, about 1:5, about 1:4, about1:3, about 1:2, about 1:1, about 2:1, about 3:1, about 4:1, about 5:1,about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 11:1,about 12:1, about 13:1, about 14:1, or about 15:1.

In one embodiment, the pharmaceutical compositions described hereincomprise a dose of an opioid (e.g., oxycodone or other opioid analgesic)and a dose of a PAMORA. In one aspect, the pharmaceutical compositionsdescribed herein comprise a dose of an opioid and a dose of a PAMORAcomprising naloxone or a pharmaceutically acceptable salt form thereof.In one aspect, the pharmaceutical compositions described herein comprisea dose of an opioid and a dose of a PAMORA comprising naltrexone or apharmaceutically acceptable salt form thereof. In another aspect, thepharmaceutical compositions described herein comprise a dose of anopioid and a dose of a PAMORA comprising methylnaltrexone or apharmaceutically acceptable salt form thereof. In another aspect, thepharmaceutical compositions described herein comprise a dose of anopioid and a dose of a PAMORA comprising naloxegol or a pharmaceuticallyacceptable salt form thereof.

In one embodiment, the pharmaceutical composition described hereincomprises a dose of naloxone and a dose of an opioid comprisingoxycodone or other opioid analgesic as described herein. In one aspect,the dose of the naloxone ranges from about 2.5 mg to about 100 mg,including each integer within the specified range. In another aspect,the dose of naloxone ranges from about 2.5 mg to about 50 mg, includingeach integer within the specified range. In another aspect, the dose ofnaloxone ranges from about 10 mg to about 50 mg, including each integerwithin the specified range. In another aspect, the dose of naloxoneranges from about 20 mg to about 40 mg, including each integer withinthe specified range. In another aspect, the dose of naloxone is about2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 15 mg, about 20 mg,about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg,about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg.

In another embodiment, the weight percentage ratio range of naloxone toopioid comprising oxycodone or other opioid analgesic in thepharmaceutical composition described herein ranges from about 1:10 toabout 5:1, including all iterations of ratios within the specifiedrange. In one aspect, the weight percentage ratio range of naloxone toopioid comprising hydrocodone or oxycodone is from about 1:5 to about1:1, including all iterations of ratios within the specified range. Inanother aspect, the weight percentage ratio range of naloxone to opioidcomprising oxycodone or other opioid analgesic is from about 1:4 toabout 1:2, including all iterations of ratios within the specifiedrange. In another aspect, the weight percentage ratio range of naloxoneto opioid comprising oxycodone or other opioid analgesic is about 1:10,about 1:9, about 1:8, about 1:7, about 1:6, about 1:5, about 1:4, about1:3, about 1:2, about 1:1, about 2:1, about 3:1, about 4:1, or about5:1. In another aspect, the weight percentage ratio range of naloxone toopioid comprising oxycodone or other opioid analgesic is about 1:2.

In another embodiment, the pharmaceutical composition described hereincomprises a dose of about 5 mg of naloxone and a dose of about 10 mg ofoxycodone. In another embodiment, the pharmaceutical compositiondescribed herein comprises a dose of about 10 mg of naloxone and a doseof about 20 mg of oxycodone. In another embodiment, the pharmaceuticalcomposition described herein comprises a dose of about 20 mg of naloxoneand a dose of about 40 mg of oxycodone. In another embodiment, thepharmaceutical composition described herein comprises a dose of about 40mg of naloxone and a dose of about 80 mg of oxycodone. In anotherembodiment, the pharmaceutical composition described herein comprises adose of about 80 mg of naloxone and a dose of about 160 mg of oxycodone.

In another embodiment, the pharmaceutical composition described hereincomprises a dose of about 5 mg of naloxone and a dose of about 10 mg ofopioid analgesic. In another embodiment, the pharmaceutical compositiondescribed herein comprises a dose of about 10 mg of naloxone and a doseof about 20 mg of opioid analgesic. In another embodiment, thepharmaceutical composition described herein comprises a dose of about 20mg of naloxone and a dose of about 40 mg of opioid analgesic. In anotherembodiment, the pharmaceutical composition described herein comprises adose of about 40 mg of naloxone and a dose of about 80 mg of opioidanalgesic. In another embodiment, the pharmaceutical compositiondescribed herein comprises a dose of about 80 mg of naloxone and a doseof about 160 mg of opioid analgesic.

In another embodiment, the pharmaceutical composition described hereincomprises a dose of about 40 mg of oxycodone and a dose of about 20 mgof naloxone. In one aspect, the composition is provided in a dosage formcontaining a total amount of about 40 mg of an oxycodone and about 20 mgof naloxone, wherein subjects administered a single dosage exhibit amean plasma oxycodone AUC_(0→∞) of about 400 h·mg/L to about 600 h·mg/Land a mean plasma naloxone AUC_(0→∞) of about 500 h·mg/L to about 600h·mg/L. In another aspect, the composition is provided in a dosage formcontaining a total amount of about 40 mg of oxycodone and about 20 mg ofnaloxone, wherein subjects administered a single dosage exhibit a meanplasma oxycodone C_(max) of about 30 ng/mL to about 50 ng/mL and a meanplasma naloxone C_(max) of about 50 ng/mL to about 70 ng/mL. In anotheraspect, the composition is provided in a dosage form containing a totalamount of about 40 mg of oxycodone and about 20 mg of naloxone, whereinsubjects administered a single dosage exhibit an oxycodone T_(max) ofabout 1 hr to about 5 hrs and a naloxone T_(max) of about 0.5 hr toabout 3 hrs.

In one embodiment, the pharmaceutical composition described hereincomprises a dose of methylnaltrexone or naltrexone and a dose of anopioid comprising opioid analgesic or oxycodone as described herein. Inone aspect, the dose of the methylnaltrexone or naltrexone ranges fromabout 2.5 mg to about 100 mg, including each integer within thespecified range. In another aspect, the dose of methylnaltrexone ornaltrexone ranges from about 50 mg to about 600 mg, including eachinteger within the specified range. In another aspect, the dose ofmethylnaltrexone or naltrexone ranges from about 100 mg to about 600 mg,including each integer within the specified range. In another aspect,the dose of methylnaltrexone or naltrexone ranges from about 300 mg toabout 600 mg, including each integer within the specified range. Inanother aspect, the dose of methylnaltrexone or naltrexone ranges fromabout 400 mg to about 600 mg, including each integer within thespecified range. In another aspect, the dose of methylnaltrexone ornaltrexone is about 50 mg, about 75 mg, about 100 mg, about 125 mg,about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg,about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg,about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg,about 525 mg, or about 550 mg.

In another embodiment, the weight percentage ratio range ofmethylnaltrexone or naltrexone to opioid comprising opioid analgesic oroxycodone in the pharmaceutical composition described herein ranges fromabout 13:1 to about 1:1, including all iterations of ratios within thespecified range. In one aspect, the weight percentage ratio range ofmethylnaltrexone or naltrexone to opioid comprising opioid analgesic oroxycodone is from about 10:1 to about 1:1, including all iterations ofratios within the specified range. In another aspect, the weightpercentage ratio range of methylnaltrexone or naltrexone to opioidcomprising opioid analgesic or oxycodone is from about 5:1 to about 1:1,including all iterations of ratios within the specified range. Inanother aspect, the weight percentage ratio range of methylnaltrexone ornaltrexone to opioid comprising opioid analgesic or oxycodone is about1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1,about 8:1, about 9:1, about 10:1, about 11:1, about 12:1, or about 13:1.

In one embodiment, the pharmaceutical composition described hereincomprises a dose of naloxegol and a dose of an opioid comprisingoxycodone or other opioid analgesic as described herein. In one aspect,the dose of the naloxegol ranges from about 2.5 mg to about 100 mg,including each integer within the specified range. In another aspect,the dose of naloxegol ranges from about 2.5 mg to about 50 mg, includingeach integer within the specified range. In another aspect, the dose ofnaloxegol ranges from about 10 mg to about 50 mg, including each integerwithin the specified range. In another aspect, the dose of naloxegolranges from about 20 mg to about 40 mg, including each integer withinthe specified range. In another aspect, the dose of naloxegol is about2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 15 mg, about 20 mg,about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg,about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg.

In another embodiment, the weight percentage ratio range of naloxegol toopioid comprising oxycodone or other opioid analgesic in thepharmaceutical composition described herein ranges from about 1:10 toabout 5:1, including all iterations of ratios within the specifiedrange. In one aspect, the weight percentage ratio range of naloxegol toopioid comprising oxycodone or other opioid analgesic is from about 1:5to about 1:1, including all iterations of ratios within the specifiedrange. In another aspect, the weight percentage ratio range of naloxegolto opioid comprising oxycodone or other opioid analgesic is from about1:4 to about 1:2, including all iterations of ratios within thespecified range. In another aspect, the weight percentage ratio range ofnaloxegol to opioid comprising oxycodone or other opioid analgesic isabout 1:10, about 1:9, about 1:8, about 1:7, about 1:6, about 1:5, about1:4, about 1:3, about 1:2, about 1:1, about 2:1, about 3:1, about 4:1,or about 5:1. In another aspect, the weight percentage ratio range ofnaloxegol to opioid comprising oxycodone or other opioid analgesic e isabout 1:2.

Another embodiment described herein is a method for treating, retardingthe progression of, prophylaxis of, delaying the onset of, ameliorating,or reducing the symptoms of pain comprising the administration of atherapeutically effective amount of one or more abuse deterrentpharmaceutical compositions described herein to a subject with pain,wherein the administration is sufficient to achieve a reduction painrelative to baseline in the subject without substantially inducing oneor more side effects including, but not limited to, headache, vertigo,somnolence, nausea, constipation, vomiting, xerostomia, fatigue,pruritus, eructation, heartburn, abdominal discomfort, or loss ofappetite.

Another embodiment described herein is a method for treating, retardingthe progression of, prophylaxis of, delaying the onset of, ameliorating,or reducing the symptoms of pain comprising the administration of atherapeutically effective amount of one or more abuse deterrentpharmaceutical compositions described herein to a subject with pain,wherein the administration is sufficient to achieve a reduction painrelative to baseline in the subject without substantially inducing oneor more side effects including, but not limited to, opioid use, such as,for example, opioid induced bowel dysfunction, opioid inducedconstipation, gastrointestinal dysfunction (e.g., inhibition ofintestinal motility, constipation, GI sphincter constriction), nausea,emesis (vomiting), biliary spasm, colic, dysphoria, pruritus, urinaryretention, depression of respiration, papillary constriction,cardiovascular effects, chest wall rigidity and cough suppression,depression of stress response, and immune suppression associated withuse of narcotic analgesia, etc, or combinations thereof.

Another embodiment described herein is a method for treating, retardingthe progression of, prophylaxis of, delaying the onset of, ameliorating,or reducing the symptoms of, irritable bowel syndrome, colitis,post-operative or postpartum ileus, nausea and/or vomiting, decreasedgastric motility and emptying, inhibition of the stomach, and smalland/or large intestinal propulsion, increased amplitude ofnon-propulsive segmental contractions, constriction of sphincter ofOddi, increased anal sphincter tone, impaired reflex relaxation withrectal distention, diminished gastric, biliary, pancreatic or intestinalsecretions, increased absorption of water from bowel contents,gastro-esophageal reflux, gastroparesis, cramping, bloating, abdominalor epigastric pain and discomfort, constipation, idiopathicconstipation, post-operative gastrointestinal dysfunction followingabdominal surgery (colectomy, e.g., right hemicolectomy, lefthemicolectomy, transverse hemicolectomy, colectomy takedown, lowanterior resection), and delayed absorption of orally administeredmedications or nutritive substances comprising the administration of atherapeutically effective amount of one or more abuse deterrentpharmaceutical compositions described herein.

Another embodiment described herein is a method for improving thequality of life of subjects receiving opioids, as well as to reducecomplications arising from chronic constipation, such as hemorrhoids,appetite suppression, mucosal breakdown, sepsis, colon cancer risk, andmyocardial infarction comprising the administration of a therapeuticallyeffective amount of one or more abuse deterrent pharmaceuticalcompositions described herein.

In another embodiment, the pharmaceutical composition described hereinprovides a dosage form comprising an opioid and a PAMORA as describedin, which in terms of efficacy, is ranked good or very good by more than50% of patients, 60%, 70%, 80%, 90%, or more of patients. In aspect, thedosage form is provided which comprises an opioid and a PAMORA asdescribed in, which in terms of tolerability, is ranked good or verygood by more than 50% of patients, 60%, 70%, 80%, 90%, or more ofpatients.

In another embodiment, the pharmaceutical composition described hereinprovides a dosage form comprising an opioid and a PAMORA as describedin, which provides a reduction of days with laxative intake by at least10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or even 90%. In one aspect, thedosage form completely reduces the need for any laxatives to be takenindependently.

In some embodiments, bowel function is assessed by observing parametersthat are associated with bowel function. In particular, bowel functionmay be determined based on parameters selected from ease or difficultyof defecation, feeling of incomplete bowel evacuation, and/or personaljudgment of patient regarding constipation. Other parameters which maybe observed alternatively or in addition in order to assess the bowelfunction of a patient include among other things stool frequency, stoolconsistency, cramping, and painful laxation. In addition, themeasurement of spontaneous bowel movements indicates improved bowelfunction.

Bowel function may be assessed by measuring parameters, which areassociated with bowel function using numerical analog scales (NAS) forthese parameters because this may provide more accurate results. Thisapproach is particularly advantageous when assessing the bowel functionin patients receiving treatment with analgesics, because analgesicefficacy of drugs is usually assessed using a numeric analog scale.

In one embodiment, a reduction in OIC is assessed by measuring a changein the spontaneous bowel movements (SBMs) frequency rate (e.g.,SBMs/week). Patients are typically classified as having OIC when havingless than 3 SBMs per week for about 4 weeks while taking an opioid. Apositive response to an OIC agent is assessed as an increase in SBMsover a period of time following the administration of the OIC agent.

In another embodiment a reduction in OIC by an anti-OIC agent isassessed by measuring the time to first SBM following administration ofthe anti-OIC agent compared to a placebo agent.

In another embodiment, a reduction in OIC by an anti-OIC agent isassessed by measuring a change in stool consistency from baseline over aperiod of time. For example, the Bristol Stool Scale may be used toassess changes.

In some embodiments, the pharmaceutical compositions comprising anopioid and an anti-OIC agent as described herein provides improvement ofthe bowel function characterized by an increase of the mean bowelfunction score of at least 5, at least about 8, at least about 10 or atleast about 15 after administration at steady state or of a single doseto human patients or healthy human subjects, wherein the mean bowelfunction score is measured with a numerical analog scale ranging from 0to 100.

In one embodiment, the bowel function is assessed by the bowel functionindex (BFI), which is measured in patients. The mean bowel functionscore may be determined by a method for assessing bowel function in apatient comprising the steps of: providing the patient with a numericanalog scale for at least one parameter, which parameter is associatedwith bowel function; causing the patient to indicate on the numericanalog scale the amount and/or intensity of the parameter beingexperienced; and observing the amount and/or intensity of the at leastone parameter indicated on the numeric analog scale in order to assessbowel function. In one aspect the patient indicates the amount and/orintensity of parameter being experienced during the last days or weeks,e.g. during the last 1, 2, 3, 4, 5, 6, 7, 10, or 14 days. In anotheraspect, the numerical analog scale on which the patient indicateshis/her subjective experience of the observed parameter may have anysize or form and may range from 0 or any other number to any number,such as from 0 to 10 or from 0 to 50 or from 0 to 300 or from 1 to 10.

In another embodiment, if more than one parameter is observed, a meanbowel function may be obtained in form of a numerical value. Thisnumerical value is the mean of the parameters observed, e.g., the threenumeric analog scale values for ease or difficulty of defecation,feeling of incomplete bowel evacuation and judgment of constipation. Theparameters, which are measures of bowel function or which are associatedwith bowel function, may comprise opioid induced bowel dysfunctions(OIBD or OIC) as described herein.

In another embodiment, bowel function may be determined based on thefollowing parameters: ease or difficulty of defecation, for exampleduring the last 7 days according to the patient assessment, wherein 0corresponds to no difficulties and 100 corresponds to severedifficulties; feeling of incomplete bowel evacuation, for example duringthe last 7 days according to the patient assessment, wherein 0corresponds to no feeling of incomplete bowel evacuation and 100corresponds to very strong feeling of incomplete bowel evacuation;personal judgment of patient regarding constipation, for example duringthe last 7 days, wherein 0 corresponds to no constipation at all and 100corresponds to very heavy constipation.

In another embodiment, bowel function may be assessed with analogsscales as described in U.S. Pat. No. 6,258,042 and International PatentApplication Publication No. WO 2003/073937, which may be adapted todevices or analog scales as described above as would be understood byone of ordinary skill in the art. The disclosures of these tworeferences are hereby incorporated by reference for such teachings.

In another embodiment, the pharmaceutical compositions described hereinfurther comprise one or more active pharmaceutical ingredient(s)comprising a PAMORA may also further limit or prevent drug abuse byinhibiting the action or effects of an opioid. The PAMORAs describedherein, for example, methylnaltrexone, naltrexone, naloxone, naloxegol,or alvimopan can function to have an aversive effect. This aversiveaffect may include any unpleasant side effect comprising inducing opioidwithdrawal symptoms, diarrhea, nausea, reduced euphoria or a mixture orcombination thereof.

In another embodiment, the abuse deterrent pharmaceutical compositiondescribed herein is contained and dispensed from a tamper evidentpackaging. The term “tamper evident” or “tamper resistant” refers to apackaging of any kind that readily displays or allows for an individualto observe any physical interference or manipulation of said packaging.The tamper evident packaging provides reasonable evidence to consumersthat tampering has occurred. The tamper evident packaging additionallycontains appropriate labelling statements describing the features andevidences of the tamper evident packaging. In one aspect, the tamperevident packaging comprises: bottles, film wrappers, blister or strippacks, bubble packs, heat shrink bands or wrappers, foil, paper, orplastic pouches, container mouth inner seals, tape seals, breakablecaps, sealed metal tubes or plastic heat-sealed tubes, sealed cartons,aerosol containers, cans including metal and composite materials, or anycombination thereof. The packaging may also contain appropriateinstructions for prescribing, instructions for use, warnings, or otherappropriate information.

It will be apparent to one of ordinary skill in the relevant art thatsuitable modifications and adaptations to the compositions,formulations, methods, processes, and applications described herein canbe made without departing from the scope of any embodiments or aspectsthereof. The compositions and methods provided are exemplary and are notintended to limit the scope of any of the specified embodiments. All ofthe various embodiments, aspects, and options disclosed herein can becombined in any and all variations or iterations. The scope of thecompositions, formulations, methods, and processes described hereininclude all actual or potential combinations of embodiments, aspects,options, examples, and preferences herein described. The exemplarycompositions and formulations described herein may omit any component,substitute any component disclosed herein, or include any componentdisclosed elsewhere herein. The ratios of the mass of any component ofany of the compositions or formulations disclosed herein to the mass ofany other component in the formulation or to the total mass of the othercomponents in the formulation are hereby disclosed as if they wereexpressly disclosed. Should the meaning of any terms in any of thepatents or publications incorporated by reference conflict with themeaning of the terms used in this disclosure, the meanings of the termsor phrases in this disclosure are controlling. Furthermore, theforegoing discussion discloses and describes merely exemplaryembodiments. All patents and publications cited herein are incorporatedby reference herein for the specific teachings thereof.

EXAMPLES Example 1

Abuse deterrent matrices as described herein were prepared using thecomposition shown in Tables 6-10. The compositions were preparedaccording to the method of Example 2 and encapsulated in a hard capsuleshell. Other suitable non-limiting capsule shells for the abusedeterrent matrices described herein comprise a soft capsule shell,enteric soft capsule shell, and an enteric hard capsule shell.

TABLE 6 Abuse Deterrent Controlled Release Matrix Compositions WeightPercentage (%) Ingredient F1 F2 F3 Capmul ® MCM  59  60  60 Polyethyleneoxide (WSR 301)  30  30  0 Polyethylene oxide (WSR 303)  0  0  30Carbopol 974P  1  0  0 Oxycodone HCl  10  10  10 TOTAL 100% 100% 100%

TABLE 7 Abuse Deterrent Controlled Release Matrix Compositions WeightPercentage (%) Ingredient F4 F5 F6 Polyethylene glycol 600  60  57.6  60Polyethylene glycol 1000  8  7.6  8 Polyvinylpyrrolidone K90  1  1  1Methocel ™ K100M  10.7 Carbopol 974P  1  5  1 Polyethylene oxide (WSR301)  10.7  9.6 Polyethylene oxide (WSR 303)  10.7  9.6  10.7 OxycodoneHCl  9  8.6  9 TOTAL 100% 100% 100%

TABLE 8 Abuse Deterrent Controlled Release Matrix Compositions WeightPercentage (%) Ingredient F7 Capmul ® MCM  63.4 Polyethylene oxide (WSR301)  27 Polyvinylpyrrolidone K90  1.25 BHA  0.25 BHT  0.10 OxycodoneHCl  8 TOTAL 100%

TABLE 9 Abuse Deterrent Controlled Release Matrix Compositions WeightPercentage (%) Ingredient F8 Oleic Acid  60.7 Ethocel ™ 20cP  1Polyethylene oxide (WSR 301)  30 BHA  0.25 BHT  0.10 Oxycodone HCl  8TOTAL 100%

TABLE 10 Abuse Deterrent Controlled Release Matrix Compositions WeightPercentage (%) Ingredient F9 Maisine ™ 35-1  60.7 Polyethylene oxide(WSR 301)  30 BHA  0.25 BHT  0.10 Oxycodone HCl  9 TOTAL 100%

TABLE 11 Abuse Deterrent Controlled Release Matrix Compositions WeightWeight (grams) Percentage (%) Ingredient F10 Oleic Acid 15.5  62Ethocel ™ 20cP 0.25  1 Polyethylene oxide (301 FP) 7.5  30 BHA 0.05  0.2BHT 0.02  0.9 Sodium lauryl sulfate 1.25  5 Hydrocodone bitartrate 0.42 1.7 TOTAL 25 100%

TABLE 12 Abuse Deterrent Controlled Release Matrix Compositions WeightPercentage (%) Ingredient F11 Soybean Oil  55.7 Ethocel ™ 20cP  20Polyethylene Glycol  20 BHA  0.25 BHT  0.10 HPMC K100M  15 Oxycodone HCl 8 TOTAL 100%

Example 2

Abuse deterrent controlled release matrix compositions as describedherein comprise one or more flowability enhancers, one or more releasemodifiers, optionally one or more viscosity modifiers, optionally one ormore antioxidants, and one or more active pharmaceutical ingredients.Flowability enhancers comprise any one or more of a medium chain mono-and di-glyceride (e.g., Capmul® MCM), oleic acid, or glycerylmonolinoleate (e.g., Maisine™ 35-1); the one or more release modifierscomprises a high molecular weight polyethylene oxide (e.g., POLYOX™ WSR301 or POLYOX™ WSR 303) and optionally a carboxyvinyl polymer (e.g.,Carbopol® 974P); the optional one or more viscosity modifiers comprisesa polyvinylpyrrolidone (e.g., polyvinylpyrrolidone K90) or anethylcellulose polymer (e.g., Ethocel™ 20 cP); the optional one or moreantioxidants comprises BHA or BHT, and the one or more activepharmaceutical ingredients comprises oxycodone or other opioidanalgesic.

Abuse deterrent controlled release matrices according to compositionsF1-F3 of Table 6 were prepared by suspending the specified amount ofCarbopol™ 974P and POLYOX™ WSR 301 or POLYOX™ WSR 303 in the specifiedamount of Capmul® MCM to form a suspension mixture. Next, the specifiedamount of oxycodone was added to the mixture and thoroughly mixed toform a final matrix fill mixture and this mixture was filled into softcapsule shells. The filled capsules were then annealed at 70° C. forabout one hour.

The abuse deterrent controlled release matrix according to compositionF7 of Table 8 was prepared by heating the specified amount of Capmul®MCM to 55° C. The specified amount of polyvinylpyrrolidone K90 was mixedin the heated Capmul® MCM until completely dissolved. Next BHA and BHTwere added until completely dissolved. The resulting mixture was cooledto approximately 30° C. and the specified amount of the activepharmaceutical ingredient oxycodone HCl was added and mixed untiluniformly dispersed. Next the polyethylene oxide 301 was added and mixeduniformly to form a suspension mixture. The resulting liquid mixture wasencapsulated as a liquid suspension and was dried and cured at a hightemperature for 45±15 minutes at 70±2° C.

The abuse deterrent controlled release matrix according to compositionF8 of Table 9 was prepared by heating the specified amount of oleic acidto 140° C. The specified amount of Ethocel™ 20 cP was mixed in theheated oleic acid until completely dissolved. This mixture was thencooled to about 85° C. and BHA and BHT was added until completelydissolved. The resulting mixture was cooled to approximately 30° C. andthe specified amount of the active pharmaceutical ingredient oxycodoneHCl and polyethylene oxide 301 was added and mixed until uniformlysuspended in a dispersion. The resulting liquid mixture was encapsulatedas a liquid suspension into soft gelatin capsules and was dried andcured for 45±15 minutes at 70±2° C.

The abuse deterrent controlled release matrix according to compositionF9 of Table 10 was prepared by heating the specified amount of Maisine™35-1 to 65° C. BHA and BHT were added until completely dissolved. Thismixture was then cooled to about 30° C. and the specified amount of theactive pharmaceutical ingredient oxycodone HCl was added and mixed untiluniformly dispersed. Next the specified amount of polyethylene oxide 301was added and mixed uniformly to form a suspension mixture. Theresulting liquid mixture was encapsulated as a liquid suspension intosoft gelatin capsules and was dried and for 45±15 minutes at 70±2° C.

The abuse deterrent controlled release matrix according to compositionF10 of Table 11 was prepared by heating the specified amount of oleicacid to 140° C. The specified amount of Ethocel™ 20 cP was mixed in theheated oleic acid until completely dissolved. This mixture was thencooled to about 85° C. and BHA and BHT was added until completelydissolved. The resulting mixture was cooled to approximately 30° C. andthe specified amount of the active pharmaceutical ingredient hydrocodonebitartrate, sodium lauryl sulfate, and polyethylene oxide 301 was addedand mixed until uniformly suspended in a dispersion. The resultingliquid mixture was encapsulated as a liquid suspension into soft gelatincapsules and was dried and cured for 45±15 minutes at 70±2° C.

The abuse deterrent matrices prior to encapsulation and annealingdemonstrated a viscous yet flowable aspect. Following the annealing stepat 70° C., the capsules demonstrated a semi-solid elastic aspect.

The process for manufacturing a soft capsule comprising the abusedeterrent matrices as described herein includes preparing a gel mass fora soft capsule; casting the gel mass into films or ribbons usingheat-controlled drums or surfaces; and manufacturing a soft capsulecomprising a matrix fill using rotary die technology. During thisprocess, the abuse deterrent controlled release matrix is injected intothe lumen as the soft capsule is formed by rotary die encapsulation. Thesoft capsule can be a typical soft capsule (“soft gel”) or an entericsoft capsule.

The melting point of PEO in different flowability enhancers includingmedium chain mono- and di-glyceride (e.g., Capmul® MCM), oleic acid, orglyceryl monolinoleate (e.g., Maisine™ 35-1) was tested. It ishypothesized that the PEO release modifier is suspended and notdissolved within the flowability enhancer throughout the processingsteps. During the annealing steps, however, the release modifier isbelieved to become molten at the two components may be miscible. Whensubsequently cooled, the release modifier subsequently recrystallizesand forms a semi-solid elastic matrix that encapsulates the flowabilityenhancer and an active pharmaceutical ingredient. To test thishypothesis, the various flowability enhancers used in the abusedeterrent matrix formulations of Tables 9-11 were tested. Thermogramsshow that PEO exhibits a surprising and significant melting pointdepression in the presence of Capmul, which impacts processability.Other flowability enhancers evaluated, including Maisine™ 35-1, oleicacid, Span® 80 and Tween® 20, also decreased the PEO melting point butto a lesser extent. An inert diluent powder, microcrystalline cellulose,was used as a control, which demonstrated no impact on the melting point(FIG. 8).

Example 4

The dissolution and release profiles under different dissolutionconditions for pharmaceutical compositions comprising the test abusedeterrent matrix compositions described in Table 6 and Table 7 are shownin FIGS. 1-7.

The percent release of oxycodone from the abuse deterrent controlledrelease matrix compositions shown in Table 6, generated by the methodsdescribed herein and encapsulated in a hard shell capsule as describedherein, were tested. As shown in FIG. 1, a test pharmaceuticalcomposition comprising the abuse deterrent matrix according to F1 ofTable 6 comprising oxycodone in an annealed capsule shell demonstrated asimilar release rate of oxycodone compared to a reference oxycodoneabuse deterrent pharmaceutical composition. The percent release ofoxycodone was determined by measuring the amount of oxycodone releasedfrom the test and reference abuse deterrent compositions in fasted statesimulated gastric fluid (FaSSGF) at pH 1.2 for two hours and in fastedstate simulated intestinal fluid (FaSSIF) at pH 6.8 for ten hoursaccording to USP specifications using Apparatus III at 30 dpm.

Next, non-annealed and annealed pharmaceutical compositions generated bythe annealing procedure described in Example 2 were tested. As shown inFIG. 2, the annealed test pharmaceutical composition comprising theabuse deterrent matrix according to F 1 of Table 6 released lessoxycodone under aqueous boiling conditions compared to a referenceoxycodone abuse deterrent composition. However, the same composition (F1of Table 6) that was not annealed demonstrated a higher release rate ascompared to both the annealed test and reference abuse deterrentcompositions. This result suggests that the annealing procedure listedin Example 2 may be one contributor to the abuse deterrent properties ofthe compositions described herein.

The effects of the viscosity modifier Carbopol® 974P on oxycodonepercent release under boiling conditions were assessed. As shown in FIG.3, the oxycodone percent release difference between the annealed testpharmaceutical composition comprising the abuse deterrent matrixaccording to F1 (1% Carbopol® 974P) and F2 (no Carbopol® 974P) of Table6 was minimal.

Next, the effects of different molecular weight polyethylene oxide inannealed test pharmaceutical compositions comprising the abuse deterrentmatrices were tested for under boiling conditions. As shown in FIG. 4,the annealed test abuse deterrent composition having higher molecularweight polyethylene oxide according to F3 of Table 6 demonstrated amodestly higher percent release of oxycodone compared to the compositionhaving lower molecular weight polyethylene oxide according to F2 ofTable 6, but was still lower than the percent release in the referenceabuse deterrent formulation after 40 minutes.

Next, the dissolution of the annealed test pharmaceutical compositioncomprising the abuse deterrent matrix according to F2 of Table 6 wastested for oxycodone release in simulated gastric fluid or in an 80%ethanol solution. As shown in FIG. 5, this test abuse deterrentcomposition demonstrated a lower percent release in ethanol compared tothe percent release in simulated gastric fluid (pH 1.2).

The percent release of oxycodone from the abuse deterrent controlledrelease matrix compositions shown in Table 7 encapsulated in a soft gelcapsule were tested in aqueous conditions at 80° C. These matrixcompositions all had reduced polyethylene oxide percentages compared tothe matrix compositions of Table 6 and demonstrated a higher percentrelease of oxycodone compared to the tested reference abuse deterrentcomposition (FIG. 6). This result indicates that higher levels ofpolyethylene oxide (e.g., 25%-30%) may also contribute to the abusedeterrent characteristics in boiling or near boiling conditions.

Next, the percent release of oxycodone from the reference abusedeterrent composition and the compositions F4-F6 of Table 7 weredetermined by conducting a dissolution test in FaSSGF at pH 1.2 for twohours and FaSSIF at pH 6.8 for ten hours according to USP specificationsusing Apparatus III at 30 dpm (FIG. 7).

Example 5

The dissolution and release profiles under different dissolutionconditions for pharmaceutical compositions comprising the test abusedeterrent matrix compositions described in Tables 8-10 corresponding toF7-F9 compared to a reference abuse deterrent matrix are shown in Table13 below and in FIG. 9. The release profiles during conditions ofnon-abuse demonstrated a low variability between each of thecompositions. The dissolution of these abuse deterrent matrices weredetermined by conducting a dissolution test in FaSSGF at pH 1.2 for twohours and FaSSIF at pH 6.8 for ten hours according to USP specificationsusing Apparatus III at 30 dpm.

TABLE 13 Dissolution % of API from Abuse Deterrent Matrix F7-F9 Time %Release % Release % Release % Release (hr) Ref F7 F8 F9 1 34 34 30 34 255 53 50 49 4 83 78 70 71 8 99 97 85 93 12 100 100 93 100

Next, the abuse deterrent properties of a pharmaceutical compositioncomprising the different abuse deterrent matrix formulations (F7-F10) ofTables 8-11 were tested. These compositions were subjected to a varietyof common physical manipulations, including crushing, grating, grindingand cutting and compared to a similarly manipulated commerciallyavailable reference abuse deterrent formulations. The test formulationswere highly resistant to crushing with a hammer due to the matrix havingrubbery, semi-solid, slippery characteristics (FIG. 10B). By comparison,a reference abuse deterrent formulation was easily crushed into powderlike smaller pieces by a hammer or a mortar and pestle (FIG. 10A). Thesmaller pieces of the reference formulation were then easily convertedto a powder using a mortar and pestle, which likely could be snorted. Incontrast, the test formulations could be cut into smaller pieces with acheese grater, coffee grinder, or other sharp cutting tools, but thesesmaller pieces would not form a powder suitable for insufflation.

The dose dumping of oxycodone from the test abuse deterrent formulations(F7-F9) of Tables 8-10 using increasing concentrations of ethanol werenext tested and compared to a commercially available reference abusedeterrent formulation containing oxycodone. These dissolutionexperiments were carried out in simulated gastric fluid (no enzymes)with 0%, 5%, 20%, and 40% ethanol using an Apparatus I (baskets) at 100RPM according to USP specifications for oxycodone HCl tablets. As shownin FIGS. 11-14, both the test abuse deterrent formulations and thereference abuse deterrent formulation demonstrated resistence to alcoholextraction or alcohol dose dumping.

Next, the extraction of oxycodone or other opioid analgesic from a testabuse deterrent formulation (F9) of Table 10 under boiling conditionswas tested and compared to commercially available reference abusedeterrent formulations containing either oxycodone or other opioidanalgesic. While intact, formulation F9 and F10 demonstratedsignificantly better boiling resistence for the extraction of oxycodonecompared to the reference formulations as shown in FIGS. 15 and 16,respectively. The test abuse deterrent formulation (F9) and thereference abuse deterrent formulation containing oxycodone were thenphysically manipulated using a mortar and pestle or a coffee grinder,respectively. An amount of each formulation corresponding to theapproximate weight of each of the intact compositions was used in anaqueous boiling extraction study. Accordingly, each formulationdemonstrated similar release kinetics (FIG. 17).

The effects of physical manipulation on the dissolution of the testabuse deterrent formulation F9 of Table 10 and formulation F10 of Table11 and a commercially available reference abuse deterrent formulationcontaining oxycodone or hydrocodone were tested. The referenceformulation was manipulated by cutting, grinding, and crushing with amortar and pestle and the test formulations (F9 and F10) weremanipulated by cutting and/or grinding with a coffee grinder. Themanipulated formulations were dissolved in an Apparatus III(reciprocating cylinder) at 30 dips per minute (most aggressive setting)in FaSSGF media and evaluated for 2 hours (FIGS. 18-22).

Next, the ability to extract and inject oxycodone from a physicallymanipulated test abuse deterrent formulation F9 of Table 10 and aphysically manipulated commercially available reference abuse deterrentformulation was assessed. The injectability/syringability of thecompositions was determined by grinding the test abuse deterrentformulation F9 of Table 10 in a coffee grinder or cutting it using asharpened edge. The reference abuse deterrent formulation wasmanipulated by crushing it with a mortar and pestle or cutting it with asharpened edge. The manipulated products were then agitated for 30minutes with a wrist action shaker at room temperature or in a waterbath shaker at 95° C. at 200 RPM. The extraction results of oxycodonefrom the various physical manipulations are shown in FIGS. 23 and 24. Itwas found that neither the test nor the reference abuse deterrentformulations were able to be drawn through a syringe connected to a 29.5gauge needle due to the high viscosity of the manipulated matrices,limiting the potential for injection (data not shown).

The test abuse deterrent formulation F9 of Table 10 was tested in anadditional injectability test, which assays whether a physicallymanipulated pharmaceutical composition can pass through a cigarettefilter and into a syringe for injection. Like the needle study, themanipulated test formulation F9 was to viscous and could not be drawninto the syringe, and thus, also passed this additional injectabilitytest (data not shown).

Example 6

Additional exemplary abuse deterrent matrix compositions useful forproducing abuse deterrent pharmaceutical compositions as describedherein are shown in Tables 14-15. Composition components are set forthby weight percentage of the total weight of the matrix mass composition.Such compositions may be encapsulated in soft capsules, enteric softcapsules, hard capsules or enteric hard capsules.

TABLE 14 Exemplary Abuse Deterrent Controlled Release MatrixCompositions Weight Percentage (%) Components EX 1 EX 2 EX 3 EX 4 EX 5EX 6 Flowability Enhancer (e.g., Capmul ® 68 65 56 50 52 40 MCM; OleicAcid; and/or Maisine 35-1) Release Modifier (e.g., Polyethylene 30 30 3030 35 50 oxide; PVP K90; and/or Ethocel ™ 20 cP) Carboxyvinyl polymers(Carbopol 1 — 4 — 3 — 974 P) BHT 0.1 0.1 0.1 0.1 0.1 0.1 BHA 0.25 0.250.25 0.25 0.25 0.25 Active Pharmaceutical Ingredient(s); 1 5 10 20 10 10(e.g., hydrocodone, oxycodone, naloxone, methylnaltrexone, naltrexone)TOTAL 100 100 100 100 100 100

TABLE 15 Exemplary Abuse Deterrent Controlled Release MatrixCompositions Weight Percentage (%) Components EX 7 EX 8 EX 9 EX 10 EX 11EX 12 Flowability Enhancer (e.g., Capmul ® 60 70 68 63 75 40 MCM; OleicAcid; and/or Maisine ™ 35-1) Release Modifier (e.g., Polyethylene 25 1522.5 27.5 23.4 40 oxide; PVP K90; and/or Ethocel ™ 20 cP) Carboxyvinylpolymers (Carbopol ® 5 5 — — — — 974 P) BHT 0.1 0.1 0.1 0.1 0.1 0.1 BHA0.25 0.25 0.25 0.25 0.25 0.25 Active Pharmaceutical Ingredient(s); 10 1010 10 1 20 (e.g., oxycodone, hydrocodone, naloxone, methylnaltrexone,naltrexone) TOTAL 100 100 100 100 100 100

Example 7

A clinical study was performed with a single-dose, five-period,five-treatment, five-way crossover relative bioavailability studycomparing four test abuse deterrent formulations (F7-F9 and F11) of a 40mg oxycodone hydrochloride capsule and compared with a commercial abusedeterrent 40 mg oxycodone tablet reference under fasted conditions

This study was a pilot, single-dose, open-label, randomized,five-period, five-treatment, five-sequence, five-way crossover study.Twenty-five healthy subjects were enrolled. Subjects who successfullycompleted the screening process checked into the research center theevening before first dose. Subjects who continued to meetinclusion/exclusion criteria the morning of dose were assigned a subjectnumber, based on the order in which they successfully completed thescreening process and procedures as outlined in the study protocol.Subjects were randomly assigned to a treatment sequence and receivedfive separate single-dose administrations of study medication, onetreatment per period, according to the randomization schedule. Dosingdays were separated by a washout period of at least 7-days. Subjectsreceived each of the treatments listed below during the five treatmentperiods as shown in Table 16.

TABLE 16 Study Treatment Protocol Treatment A: FORMULATION F11 Oxycodonehydrochloride extended- release capsule, 40 mg Dose = 1 × 40 mg capsuleTreatment B: FORMULATION F8 Oxycodone hydrochloride extended- releasecapsule, 40 mg Dose = 1 × 40 mg capsule Treatment C: FORMULATION F9Oxycodone hydrochloride extended- release capsule, 40 mg Dose = 1 × 40mg capsule Treatment D: FORMULATION F7 Oxycodone hydrochloride extended-release capsule, 40 mg Dose = 1 × 40 mg capsule Treatment E: ReferenceProduct Commercial (oxycodone hydrochloride) extended-release tablet, 40mg Dose = 1 × 40 mg tabletClinical Procedures Summary

During each study period, 4 mL blood samples were obtained prior to eachdosing and following each dose at selected times through 36-hourspost-dose. A total of 95 pharmacokinetic blood samples were to becollected from each subject, 19 samples in each study period. Inaddition, blood was drawn and urine was collected for clinicallaboratory testing at screening and study exit.

In each study period, subjects were admitted to the study unit in theevening prior to the scheduled dose. Subjects were confined to theresearch center during each study period until completion of the 36-hourblood collection and other study procedures.

Procedures for Collecting Samples for Pharmacokinetic Analysis

Blood samples (1×4 mL) were collected in vacutainer tubes containingK₂-EDTA as a preservative at pre-dose (0) and at 0.5, 1, 1.5, 2, 2.5, 3,3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 12, 18, 24, and 36-hours after dosing.

Bioanalytical Summary

Plasma samples were analyzed for oxycodone by Worldwide Clinical TrialsEarly Phase Services/Bioanalytical Sciences, Inc. (WCT) using avalidated LC-MS mass spectrometry procedure. The method was validatedfor a range of 0.250 to 125 ng/mL for oxycodone, based on the analysisof 0.250 mL of human EDTA plasma. Data were stored in Watson LaboratoryInformation Management System (LIMS; Version 7.2.0.03, Thermo FisherScientific).

Pharmacokinetic Analysis

Concentration time data were transferred from Watson LaboratoryInformation Management System directly to Phoenix™ WinNonlin® (Version6.3, Pharsight Corporation) using the Custom Query Builder option foranalysis. Data were analyzed by noncompartmental methods in WinNonlin.Concentration time data that were below the limit of quantification(BLQ) were treated as zero in the data summarization and descriptivestatistics. In the pharmacokinetic analysis, BLQ concentrations weretreated as zero from time-zero up to the time at which the firstquantifiable concentration was observed; embedded and/or terminal BLQconcentrations were treated as “missing”. Full precision concentrationdata (not rounded to three significant figures) and actual sample timeswere used for all pharmacokinetic and statistical analyses.

The following pharmacokinetic parameters were calculated: peakconcentration in plasma (C_(max)), time to peak concentration (T_(max)),elimination rate constant (λ_(z)), terminal half-life (t_(1/2)), areaunder the concentration-time curve from time-zero to the time of thelast quantifiable concentration (AUC_(last)), and area under the plasmaconcentration time curve from time-zero extrapolated to infinity(AUC_(0→∞)).

Analysis of variance (ANOVA) and the Schuirmann's two one sided t-testprocedures at the 5% significance level were applied to thelog-transformed pharmacokinetic exposure parameters, C_(max),AUC_(last), and AUC_(0→∞). The 90% confidence interval for the ratio ofthe geometric means (Test/Reference) was calculated. Bioequivalence wasdeclared if the lower and upper confidence intervals of thelog-transformed parameters were within 80% to 125%.

Example 8

The test abuse-deterrent formulations F7-F9 described herein were testedfor in vivo bioequivalence to a commercially available reference productand a comparative formulation F11. Data from 25 subjects who completedat least one study period were included in the pharmacokinetic andstatistical analyses. Mean concentration-time data are shown in Table 17and FIGS. 25-26. Results of the pharmacokinetic and statistical analysesare shown below in Tables 18-22.

The 90% confidence interval for comparing the maximum exposure, based onln(C_(max)), is within the accepted 80% to 125% limits for TreatmentsFORMULATION F9 and FORMULATION F7.

The 90% confidence intervals for comparing total systemic exposure,based on ln(AUC_(last)) and ln(AUC_(0→∞)), are within the accepted 80%to 125% limits for all test formulations. Therefore, test formulationsFORMULATION F9 and FORMULATION F7 of oxycodone hydrochlorideextended-release capsule are bioequivalent to a commercial oxycodoneproduct under fasted conditions.

TABLE 17 Oxycodone Concentration-Time Data after Administration ofFORMULATION F11 (Treatment A), FORMULATION F8 (Treatment B), FORMULATIONF9 (Treatment C), FORMULATION F7 (Treatment D), and the CommerciallyAvailable Reference Product (Treatment E) Time Mean SD CV (h) n (ng/mL)(ng/mL) (%) Treatment A: FORMULATION F11 0.00 23 0.00 0.00 NC 0.50 232.18 4.24 193.98 1.00 23 26.1 17.5 66.89 1.50 23 41.1 17.8 43.28 2.00 2354.0 26.0 48.18 2.50 23 57.8 23.0 39.86 3.00 23 60.5 18.7 30.91 3.50 2358.2 16.9 29.10 4.00 23 56.9 13.3 23.31 4.50 23 55.3 15.5 28.00 5.00 2350.4 15.0 29.69 5.50 23 45.2 15.2 33.57 6.00 23 41.0 13.6 33.07 7.00 2334.3 12.9 37.59 8.00 23 28.3 11.5 40.67 12.00 23 12.0 6.45 53.76 18.0023 4.18 2.86 68.40 24.00 23 1.57 1.28 81.99 36.00 23 0.226 0.333 147.23Treatment B: FORMULATION F8 0.00 23 0.00 0.00 NC 0.50 23 1.72 1.80104.64 1.00 23 13.8 8.76 63.69 1.50 23 22.5 12.4 54.92 2.00 23 28.7 13.346.50 2.50 23 32.2 13.3 41.29 3.00 23 34.8 12.2 35.03 3.50 23 36.3 11.631.95 4.00 23 37.1 11.9 32.04 4.50 23 38.1 13.6 35.60 5.00 23 37.2 13.436.11 5.50 23 35.4 11.6 32.75 6.00 23 33.5 10.8 32.31 7.00 23 31.4 9.5130.33 8.00 23 29.5 8.92 30.24 12.00 23 20.1 6.65 33.09 18.00 23 10.45.32 51.34 24.00 23 4.98 3.62 72.61 36.00 23 0.893 0.734 82.20 TreatmentC: FORMULATION F9 0.00 25 0.00 0.00 NC 0.50 25 4.33 7.96 183.53 1.00 2516.9 11.4 67.30 1.50 25 23.5 10.3 43.94 2.00 25 29.3 8.40 28.64 2.50 2533.5 8.16 24.34 3.00 25 35.8 8.15 22.76 3.50 25 36.6 8.50 23.23 4.00 2537.4 9.21 24.66 4.50 25 40.5 10.2 25.28 5.00 25 41.3 11.5 27.87 5.50 2540.4 10.5 26.09 6.00 25 39.5 11.1 28.15 7.00 25 36.7 10.2 27.73 8.00 2531.7 9.04 28.49 12.00 25 18.5 6.15 33.22 18.00 25 8.65 4.76 55.07 24.0025 3.83 2.54 66.39 36.00 25 0.653 0.562 86.17 Treatment D: FORMULATIONF7 0.00 23 0.00 0.00 NC 0.50 23 3.77 4.19 111.10 1.00 23 18.4 8.21 44.661.50 23 27.2 8.95 32.92 2.00 23 33.6 9.79 29.11 2.50 23 38.5 11.3 29.323.00 23 41.0 10.7 26.07 3.50 23 42.6 11.7 27.50 4.00 23 43.7 12.0 27.574.50 23 47.6 13.4 28.21 5.00 23 46.8 12.9 27.68 5.50 23 44.7 12.3 27.496.00 23 42.6 12.6 29.62 7.00 23 37.9 11.2 29.47 8.00 23 33.3 9.73 29.2212.00 23 18.0 4.41 24.47 18.00 23 7.07 2.21 31.28 24.00 23 2.80 0.96334.40 36.00 23 0.469 0.291 62.14 Treatment E: Commercially AvailableReference Product 0.00 23 0.00 0.00 NC 0.50 23 7.04 5.73 81.40 1.00 2317.6 7.06 40.20 1.50 23 24.7 10.5 42.39 2.00 23 29.8 11.6 38.91 2.50 2336.0 11.3 31.30 3.00 23 40.4 13.0 32.11 3.50 23 42.8 10.0 23.36 4.00 2345.2 8.91 19.72 4.50 23 48.5 10.7 22.06 5.00 23 47.7 10.9 22.83 5.50 2343.3 9.96 23.00 6.00 23 41.2 9.30 22.60 7.00 23 36.3 8.49 23.39 8.00 2331.4 7.76 24.74 12.00 23 15.9 5.97 37.62 18.00 23 6.01 3.09 51.34 24.0023 2.21 1.43 64.48 36.00 23 0.313 0.346 110.42 *Plasma samples analyzedusing a bioanalytical method with a validated range 0.250 to 125 ng/mL;concentrations reported in ng/mL to 3 significant figures;concentrations below limit of quantification set to zero (0.00 ng/mL) inthe data summarization ** NC = Not calculated

TABLE 18 Pharmacokinetic Parameters of Oxycodone Treatment A: TreatmentB: FORMULATION F11 FORMULATION F8 Parameter n Mean SD CV% n Mean SD CV%T_(max) (h) 23 2.90 0.84 28.99 23 4.17 1.56 37.29 C_(max) (ng/mL) 2369.3 19.0 27.40 23 41.2 14.3 34.67 AUC_(last) (h * ng/mL) 23 487.1 161.133.08 23 501.7 135.4 26.99 AUC_(0→∞) (h * ng/mL) 23 491.3 162.2 33.01 23509.1 139.3 27.36 AUC_(Extrap) (%) 23 0.90 0.37 40.85 23 1.37 1.06 77.24λ_(z) (h⁻¹) 23 0.1720 0.0303 17.60 23 0.1469 0.0258 17.56 t_(1/2) (h) 234.16 0.78 18.69 23 4.87 0.96 19.73 T_(last) (h) 23 29.22 6.08 20.82 2335.48 2.50 7.05 C_(last) (ng/mL) 23 0.731 0.338 46.16 23 0.968 0.72675.08 Treatment C: Treatment D: FORMULATION F9 FORMULATION F7 Parametern Mean SD CV% n Mean SD CV% T_(max) (h) 25 4.88 1.10 22.55 23 4.46 0.9421.10 C_(max) (ng/mL) 25 43.6 11.0 25.33 23 50.0 13.4 26.85 AUC_(last)(h * ng/mL) 25 496.6 141.4 28.47 23 506.3 116.4 22.99 AUC_(0→∞) (h *ng/mL) 25 503.2 143.7 28.56 23 510.6 116.8 22.88 AUC_(Extrap) (%) 251.28 0.80 62.95 23 0.86 0.53 61.71 λ_(z) (h⁻¹) 25 0.1534 0.0296 19.30 230.1566 0.0200 12.80 t_(1/2) (h) 25 4.71 1.05 22.35 23 4.49 0.56 12.36T_(last) (h) 25 33.61 4.90 14.59 23 34.43 4.13 12.00 C_(last) (ng/mL) 250.940 0.559 59.45 23 0.665 0.410 61.57 Treatment E: Reference ProductParameter n Mean SD CV% T_(max) (h) 23 4.37 0.72 16.59 C_(max) (ng/mL)23 50.6 11.3 22.40 AUC_(last) (h * ng/mL) 23 471.0 125.0 26.55 AUC_(0→∞)(h * ng/mL) 23 475.9 125.8 26.44 AUC_(Extrap) (%) 23 1.04 0.53 50.51λ_(z) (h⁻¹) 23 0.1723 0.0272 15.76 t_(1/2) (h) 23 4.12 0.63 15.26T_(last) (h) 23 30.79 6.08 19.75 C_(last) (ng/mL) 23 0.850 0.453 53.34

TABLE 19 Statistical Analysis of the Log-Transformed Systemic ExposureParameters of Oxycodone Comparing FORMULATION F11 (Treatment A) to theReference Product (Treatment E) Dependent Geometric Mean^(a) Ratio(%)^(b) 90% CI^(c) ANOVA Variable Test Ref (Test/Ref) Lower Upper PowerCV% ln(C_(max))  66.3159  49.0244 135.27 126.68 144.44 0.9999 13.38ln(AUC_(last)) 465.1938 457.8338 101.61  97.31 106.09 1.0000  8.79ln(AUC_(0→∞)) 469.4403 462.6757 101.46  97.20 105.91 1.0000  8.73^(a)Geometric Mean for FORMULATION F11 (Test) and Reference Product(Ref) based on Least Squares Mean of log-transformed parameter values^(b)Ratio (%) = Geometric Mean (Test)/Geometric Mean (Ref) ^(c)90%Confidence Interval

TABLE 20 Statistical Analysis of the Log-Transformed Systemic ExposureParameters of Oxycodone Comparing FORMULATION F8 (Treatment B) to theReference Product (Treatment E) Dependent Geometric Mean^(a) Ratio(%)^(b) 90% CI^(c) ANOVA Variable Test Ref (Test/Ref) Lower Upper PowerCV% ln(C_(max))  38.9240  49.0244  79.40  74.36  84.78 0.9999 13.38ln(AUC_(last)) 488.7861 457.8338 106.76 102.25 111.47 1.0000  8.79ln(AUC_(0→∞)) 495.7325 462.6757 107.14 102.65 111.84 1.0000  8.73^(a)Geometric Mean for FORMULATION F11 (Test) and Reference Product(Ref) based on Least Squares Mean of log-transformed parameter values^(b)Ratio (%) = Geometric Mean (Test)/Geometric Mean (Ref) ^(c)90%Confidence Interval

TABLE 21 Statistical Analysis of the Log-Transformed Systemic ExposureParameters of Oxycodone Comparing FORMULATION F9 (Treatment C) to theReference Product (Treatment E) Dependent Geometric Mean^(a) Ratio(%)^(b) 90% CI^(c) ANOVA Variable Test Ref (Test/Ref) Lower Upper PowerCV% ln(C_(max))  42.2828  49.0244  86.25  80.79  92.07 0.9999 13.38ln(AUC_(last)) 479.8001 457.8338 104.80 100.38 109.41 1.0000  8.79ln(AUC_(0→∞)) 486.0219 462.6757 105.05 100.64 109.64 1.0000  8.73^(a)Geometric Mean for FORMULATION F11 (Test) and Reference Product(Ref) based on Least Squares Mean of log-transformed parameter values^(b)Ratio (%) = Geometric Mean (Test)/Geometric Mean (Ref) ^(c)90%Confidence Interval

TABLE 22 Statistical Analysis of the Log-Transformed Systemic ExposureParameters of Oxycodone Comparing FORMULATION F7 (Treatment D) to theReference Product (Treatment E) Dependent Geometric Mean^(a) Ratio(%)^(b) 90% CI^(c) ANOVA Variable Test Ref (Test/Ref) Lower Upper PowerCV% ln(C_(max))  48.0481  49.0244  98.01  91.79 104.65 0.9999 13.38ln(AUC_(last)) 493.6964 457.8338 107.83 103.27 112.59 1.0000  8.79ln(AUC_(0→∞)) 497.9574 462.6757 107.63 103.11 112.34 1.0000  8.73^(a)Geometric Mean for FORMULATION F11 (Test) and Reference Product(Ref) based on Least Squares Mean of log-transformed parameter values^(b)Ratio (%) = Geometric Mean (Test)/Geometric Mean (Ref) ^(c)90%Confidence Interval

Example 9

Based on the results of the pilot study, the formulation shown in Table23 was prepared for pivotal bioequivalence studies. The formulation wasencapsulated in a soft gelatin capsule, coated with a polyvinyl alcoholcoating (e.g., Opadry® amb II, Colorcon) to provide a 10-12% weightgain, and then annealed in the coating pan by heating the capsules to65-70° C. for about 30 min to about 90 min, then slowly cooling thecapsules to room temperature by reducing the temperature 5° C. over a 5min to 15 min period (e.g., a 0.3-1° C. decrease per min).

TABLE 23 Oxycodone Hydrochloride Clinical Formulation Dosage 40 mgoxycodone hydrochloride Component Mass (mg) % weight Glycerylmonolinoleate 201.1  57.5 (Maisine ™) PEO 301 FP 105.0  30.0 BHA 1.1 0.31 BHT 0.4  0.13 Oxycodone HCl 42.4  12.1 TOTAL 350.0 100.0% RatioPEO:Maisine ™ 35-1 1:1.9 Ratio API:PEO 1:2.5

Example 10

Based on the results of the pilot study, a single-dose, open-label,three-way crossover bioequivalence study involving three-period,two-sequence, three-treatment was conducted with the dosage formdescribed in Table 23.

In the first two periods, the subjects received a single dose ofoxycodone 40 mg extended-release capsules (Banner Life Sciences; Table23) or OXYCONTIN® (oxycodone hydrochloride) 40 mg extended-releasetablets (Purdue Pharma L.P.) under fasting conditions in a randomized,crossover fashion with balanced sequence. In the third period, allsubjects received a single dose of oxycodone 40 mg extended-releasecapsules (Banner Life Sciences) with a high-fat meal according to theFDA Guidance on food effect evaluation. Twenty-six subjects wereenrolled.

Healthy, non-smoking (for at least 6 months prior to first study drugadministration), male and non-pregnant female volunteers, 18-55 years ofage, inclusive, with a body mass index (BMI) within 18-33 kg/m²,inclusive. Six (6) additional subjects were on stand-by. All eligiblesubjects took naltrexone hydrochloride (Accord Healthcare, Inc., U.S),both at −13 hours and at −1 hour prior to Period 1 study drugadministration to ensure that at least 26 qualified subjects wouldcontinue study participation, who in the opinion of thePI/Sub-Investigator, did not experience side effects that would precludethem from advancing in the study based on safety concerns. Once 26subjects have received the study drug in Period 1, the remainingsubjects were released from the study.

The assignment of treatment groups (randomization scheme) was begenerated by a computer program designed and run in SAS® Version 9.4 atBPSI. This was an open-label study and subjects as well as clinic staffwere not be blinded to the randomization. The bioanalytical laboratorystaff was blinded and did not have access to the randomization schemeuntil the bioanalytical analysis is complete.

Subjects who met the eligibility criteria were be assigned equally intoone of the following two sequence groups:

Period 1 Period 2 Period 3 Sequence 1 A B C Sequence 2 B A C

Each subject received a total of three treatments by the end of thestudy.

Treatment Code A (Test) B (Reference) C (Test) Drug Name: OxycodoneOXYCONTIN ® Oxycodone hydrochloride (oxycodone hydrochloridehydrochloride) Strength: 40 mg 40 mg 40 mg Dosage Form: Extended-Extended- Extended- release release release capsules tablets capsulesManufactured Banner Life Purdue Pharma Banner Life by/for: Sciences L.P.Sciences Dose: 1 × 40 mg 1 × 40 mg 1 × 40 mg under fasting under fastingunder fed conditions conditions conditions Treatment Opioid AntagonistDrug Name: Naltrexone hydrochloride Strength: 50 mg Dosage Form:Film-coated tablets Manufactured Accord Healthcare, Inc., U.S. by/for:Dose: 1 × 50 mgFasting Conditions

Following at least a 10-hour overnight fasting period, subjects weredosed and were required to continue to fast for at least 4 hours afterdosing.

Following the fasting period of at least 4-hours after dosing, subjectswere given standardized meals and caffeine/methylxanthine-free beveragesat scheduled times. In this study, meals were served at approximately−14.5 and −11 hours prior to study drug administration and atapproximately 4.5, 9.5, 13.5, 24, 28.5, 33.5 (Only for Period 3) and37.5 hours after dosing. Meals and beverages during confinement wereidentical between each study period. Except for water given with studymedication, no fluid was allowed from 1 hour before dosing until 1-hourpost-dose. Water was allowed/provided ad libitum at all other times.

Fed Conditions

Following at least a 10-hour overnight fasting period, subjects willstart an FDA-recommended high-fat, high-calorie breakfast 30 minutesprior to dosing. Study subjects completely consumed this high fat mealwithin 30 minutes or less. The drug products were administered 30minutes after the start of the high fat/high calorie breakfast.

Following a fasting period of at least 4-hours after dosing, subjectswere given standardized meals and caffeine/methylxanthine-free beveragesat scheduled times. Meals were served at approximately −14.5 and −11hours prior to study drug administration and at approximately 4.5, 9.5,13.5, 24, 28.5, 33.5 (Only for Period 3) and 37.5 after dosing. Mealsand beverages during confinement were identical between each studyperiod.

No food was allowed from at least 10 hours before the FDA-recommendedhigh-fat, high-calorie breakfast. Except for the fluids served withbreakfast and the water given with study medication, no fluid wasallowed from 1 hour before dosing until 1-hour post-dose. Water wasallowed/provided ad libitum at all other times.

Procedures for Collecting Samples for Pharmacokinetic Analysis

Blood were obtained by direct venipuncture in the arm. Blood samples(1×4 mL) were collected in vacutainer tubes containing K₂-EDTA as apreservative at pre-dose (0; within 2-hours pre-dosing) and at 0.5, 1,1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 12, 18, 24, and 36-hoursafter dosing.

Plasma samples were assayed for oxycodone using a validated analyticalmethod according to the principles of Good Laboratory Practice.

Data from the following subjects were included in the finalpharmacokinetics and statistical analyses:

-   -   1. Subjects who completed at least two study periods with test        formulation and reference formulation under same        gastrointestinal condition or test formulation under different        gastrointestinal condition.    -   2. Subjects who missed samples that have been pre-determined        prior to the start of bioanalytical analysis to not        significantly impact the overall outcome of the study.        Data from subjects who were dismissed or withdrew due to AE(s)        were not be included in the PK and statistical analysis.

Pharmacokinetic parameters were calculated using non-compartmentalanalysis (NCA) method using SAS® Version 9.4. The followingpharmacokinetic parameters were estimated for oxycodone and included inthe pharmacokinetic and statistical analysis for the subjects in thefinal data set:

-   -   C_(max): The maximal observed plasma concentration.    -   T_(max): Time when the maximal plasma concentration is observed.    -   AUC_(0→τ): Area under the concentration-time curve from time        zero until the last measurable concentration or last sampling        time τ, whichever occurs first. AUC_(0→τ) is estimated using the        trapezoidal method.    -   AUC_(0→∞): Area under the concentration-time curve from time        zero to infinity, calculated as AUC_(0→τ)+C_(last)/λ, where        C_(last) is the last measurable concentration.    -   λ: Terminal elimination rate constant, estimated by linear        regression analysis of the terminal portion of the natural log        of concentration (ln-concentration) vs. time plot.    -   t_(1/2): Terminal elimination half-life, estimated as ln(2)/λ.

During pharmacokinetic and statistical analyses, drug concentrationsbelow the lower limit of quantitation of the assay were considered aszero prior to the first measurable concentration. Drug concentrationsthat were below the limit of quantitation following a measurable resultwere considered as missing during pharmacokinetic calculations andestimations.

Missed samples and non-reportable concentrations (e.g. quantity notsufficient) from the analytical laboratory were treated in thepharmacokinetic analysis as if they had not been scheduled forcollection.

The λ, t_(1/2), and AUC_(0→∞) parameters were not estimated for plasmaconcentration-time profiles where the terminal linear phase was notclearly defined (R<0.8).

Descriptive statistics (min., max., median, mean, standard deviation,and coefficient of variability) of all pharmacokinetic parameters werecalculated for monomethyl fumarate for the Test and Reference products.

ANOVA including sequence, subjects nested within sequence, period andtreatment were performed on the ln-transformed data for AUC_(0→τ),AUC_(0→∞), and C_(max) and on the untransformed data for T_(max), λ, andt_(1/2). T_(max) was analyzed using the non-parametric Wilcoxon test.

The 90% Confidence Interval of the Test/Reference ratios of geometricmeans for AUC_(0→τ), AUC_(0→∞), and C_(max) was calculated based on theLSMEANS and ESTIMATE of the ANOVA. Additional statistical and alternatetests were performed as necessary.

Bioequivalence between Test (A) and Reference (B) products isdemonstrated under fasting conditions when the 90% CI for the AB ratiosof geometric least-squares means for AUC_(0→τ), AUC_(0→∞), and C_(max)are completely contained within the U.S. FDA defined acceptance range of80.00%-125.00% for oxycodone.

Example 11

Comparative Bioavailability Study Results

Mean plasma oxycodone concentrations from the bioavailability studydescribed in Example 10 are shown in Tables 24-26. The mean plasmaoxycodone concentration data are plotted in FIGS. 29 and 30,respectively. The reference drug (B, Reference) in both studies isOXYCONTIN® (oxycodone hydrochloride) 40 mg extended-release tablets, CII(Purdue Pharma L.P.). Pharmacokinetic parameters are shown in Tables27-28 for the Tests and Reference.

TABLE 24 Mean Plasma Oxycodone Concentration as a Function of Time afterDosing A Test (Fasted) Time Mini- Maxi- Std. Coeff. of Variable (h) Nmum mum Mean Dev. Variation C1 Pre- 26 0 0.81 0.07 0.19 269.58 dose C2 0.5 26 0 4.41 0.42 0.94 221.67 C3  1.0 26 0 28.81 10.48 8.66 82.69 C4 1.5 26 0 43.33 19.79 11.9 60.11 C5  2.0 26 0 51.84 27.37 13.08 47.78 C6 2.5 26 0 61.85 33.26 14.92 44.85 C7  3.0 26 3.4 67.69 36.15 13.78 38.11C8  3.5 26 19.15 65.51 38.38 11.7 30.48 C9  4.0 26 23.93 67.01 39.4811.39 28.85 C10  4.5 26 23.63 66.32 40.66 11.27 27.72 C11  5.0 26 24.4474.2 43.05 12.07 28.04 C12  5.5 26 24.71 73.04 42.71 12.02 28.14 C13 6.0 26 22.36 67.57 39.73 11.27 28.35 C14  7.0 26 21.07 56.38 34.6 9.7728.24 C15  8.0 26 18 41.41 28.86 6.94 24.04 C16 12.0 26 6.7 23.53 14.74.71 32.06 C17 18.0 26 1.97 9.67 5.68 2.42 42.55 C18 24.0 26 0.72 4.442.19 1.1 50.42 C19 36.0 26 0 0.78 0.31 0.28 89.76

TABLE 25 Mean Plasma Oxycodone Concentration as a Function of Time afterDosing B Reference (Fasted) Vari- Time Mini- Maxi- Std. Coeff. of able(h) N mum mum Mean Dev. Variation C1 Pre- 26 0  0.28  0.01 0.05 509.9dose C2  0.5 26 0.66 14.45  4.09 3.51 85.81 C3  1.0 26 4.86 38.35 16.528.8 53.27 C4  1.5 26 11.23 46.21 22.73 9.75 42.91 C5  2.0 26 11.2 60.2728.38 11.13 39.22 C6  2.5 26 13.04 67.82 31.46 10.62 33.77 C7  3.0 2617.98 70.57 35.92 9.64 26.83 C8  3.5 26 21.51 69.79 37.36 9.02 24.15 C9 4.0 26 21.92 75.07 38.07 10.22 26.85 C10  4.5 26 25.71 70.87 38.65 9.3824.27 C11  5.0 26 25.19 68.07 39.84 10.35 25.97 C12  5.5 26 22.1 63.5338.86 10.38 26.71 C13  6.0 26 20.91 61.07 36.7  9.96 27.15 C14  7.0 2618.65 51.79 31.88 8.08 25.34 C15  8.0 26 17.89 45.48 27.65 7.38 26.69C16 12.0 26 7.57 27.21 15.34 5.11 33.3 C17 18.0 26 2.56 12.88  6.51 2.4737.88 C18 24.0 26 0.93  5.65  2.79 1.25 44.67 C19 36.0 26 0  1.78  0.440.39 88.04

TABLE 26 Mean Plasma Oxycodone Concentration as a Function of Time afterDosing C Test (Fed) Vari- Time Mini- Maxi- Std. Coeff. of able (h) N mummum Mean Dev. Variation C1 Pre- 26 0 0.53  0.12  0.17 135.68 dose C2 0.5 26 0 0.58  0.04  0.13 303.47 C3  1.0 26 0 15.76  1.79  3.68 206.37C4  1.5 26 0 39.67 10.5  10.56 100.53 C5  2.0 26 0 110.66 26.62 24.1290.61 C6  2.5 26 0.36 93.17 35.57 23.99 67.46 C7  3.0 26 1.48 87.0641.37 21.71 52.48 C8  3.5 26 7.6 89.26 48.22 19.34 40.1 C9  4.0 26 25.2985.98 51.82 14.76 28.49 C10  4.5 26 36.81 81.69 54.08 12.25 22.66 C11 5.0 26 36.85 82.93 58.32 11.39 19.53 C12  5.5 26 35.1 76.76 54.63 11.0320.2 C13  6.0 26 32.16 70.05 50.95 10.99 21.56 C14  7.0 26 25.72 63.7343.61 10.75 24.66 C15  8.0 26 20.57 56.5 36.79 9.6 26.09 C16 12.0 267.75 27.82 15.96  5.45 34.14 C17 18.0 26 2.63 10.51  5.73  2.29 40.06C18 24.0 26 0.74 4.51 2.2  0.96 43.66 C19 36.0 26 0 1.05  0.37  0.2875.25

TABLE 27 Pharmacokinetic Parameters for Plasma Oxycodone AUC_(τ) AUC_(∞)C_(max) AUC_(τ) (h · ng/ (h · ng/ (ng/m T_(max) (h · ng/ λ_(z) t_(1/2)ln ln ln mL) mL) L) (h)* mL) (1/h)* (h)* (AUC_(τ)) (AUC_(∞)) (C_(max)) ATest (Fasted) N 26 26 26 26 26 26 26 26 26 26 Max 658.33 662.43 0.996874.2 7 0.2371 5.42 6.4897 6.4959 4.3068 Min 248.62 257.8 0.9644 25.962.5 0.1278 2.92 5.5159 5.5522 3.2566 Median 436.66 442.63 0.9905 43.94 50.1574 4.4 6.0791 6.0927 3.7827 Mean 428.81 433.53 0.988 45.99 4.630.1625 4.36 6.0253 6.0374 3.7974 Std. Dev. 114.63 114.13 0.0078 11.941.12 0.026 0.62 0.2762 0.2713 0.2531 CV % 26.73 26.33 0.79 25.96 24.1716.03 14.33 4.58 4.49 6.67 B Reference (Fasted) N 26 26 26 26 26 26 2626 26 26 Max 760.14 764.18 0.996 75.07 5.53 0.1945 7.59 6.6335 6.63884.3184 Min 259.4 267.95 0.9493 28.49 2 0.0913 3.56 5.5584 5.5908 3.3496Median 428.28 430.29 0.9922 41.41 5 0.1581 4.38 6.0597 6.0644 3.7234Mean 435.2 440.68 0.9867 42.03 4.56 0.1539 4.62 6.0466 6.0601 3.71 Std.Dev. 109.41 109.07 0.0117 10.73 0.92 0.0233 0.85 0.2456 0.2415 0.2382 CV% 25.14 24.75 1.19 25.52 20.19 15.11 18.46 4.06 3.99 6.42 C Test (Fed) N26 26 26 26 26 26 26 26 26 26 Max 658.33 662.43 0.9968 74.2 7 0.23715.42 6.4897 6.4959 4.3068 Min 248.62 257.8 0.9644 25.96 2.5 0.1278 2.925.5159 5.5522 3.2566 Median 436.66 442.63 0.9905 43.94 5 0.1574 4.46.0791 6.0927 3.7827 Mean 428.81 433.53 0.988 45.99 4.63 0.1625 4.366.0253 6.0374 3.7974 Std. Dev. 114.63 114.13 0.0078 11.94 1.12 0.0260.62 0.2762 0.2713 0.2531 CV % 26.73 26.33 0.79 25.96 24.17 16.03 14.334.58 4.49 6.67

TABLE 28 Summary of Comparative Bioavailability Analysis for OxycodoneRandomized, 4-way crossover, open-label, single-dose, fasting designGeometric Mean *Arithmetic Mean (% CV) AUC_(0→τ) AUC_(0→∞) C_(max)T_(max) t_(1/2) λ_(z) AUC_(0-τ)/ Sample (h · ng/mL) (h · ng/mL) (ng/mL)(h)* (h)* (1/h)* AUC_(0-∞)† A Test 413.76 418.81 44.58 5.00 4.36 0.16250.9880 (Fasted) 428.81 433.53 45.99 (2.50-7.00) (14.33) (16.03) (0.79)(26.73) (26.33) (25.96) C Test 486.29 490.61 60.57 4.53 4.56 0.15690.9912 (Fed) 499.59 503.73 62.24 (2.03-6.00) (16.93) (19.29) (0.57)(23.09) (22.85) (24.79) B 422.68 428.4 40.85 5.00 4.62 0.1539 0.9867Reference 435.2 440.68 42.03 (2.00-5.53) (18.46) (15.11) (1.19) (25.14)(24.75) (25.52) Ratio of Geometric 90% Confidence Intra-subject CV Means(Test:Ref) Interval (%) A Test/B AUC_(0-τ)  97.89  93.00-103.04 10.85Reference AUC_(0-∞)  97.76  92.98-102.79 10.62 C_(max) 109.13102.39-116.31 13.51 Ratio of Geometric 90% Confidence Intra-subject CVMeans (Fasted:Fed) Interval (%) A Test/ AUC_(0-τ) 117.5  103.96-132.8726.33 C Test AUC_(0-∞) 117.14 103.81-132.19 25.93 C_(max) 135.87121.02-152.53 24.79 Test A, C: oxycodone hydrochloride, 40 mgextended-release capsules. See Table 23. Reference: OXYCONTIN ®(oxycodone hydrochloride) 40 mg extended-release tablets, CII (PurduePharma L.P.). * Arithmetic mean (% CV) only †Median and range only

Example 9

Abuse deterrent dosage forms were prepared using the compositions shownin Table 29 and encapsulated in a soft capsule shell with a polyvinylalcohol coating as a moisture barrier. The dosage forms were annealed inthe coating pan after coating at 60-70° C. for 30 to 90 min and thenslowly cooled to room temperature (dropping about 5° C. every 5 to 15min.).

TABLE 29 Abuse Deterrent Controlled Release Oxycodone CompositionsDosage 10 mg 15 mg Component Mass (mg) % weight Mass (mg) % weightGlyceryl monolinoleate 222.0  63.4 218.5  62.4 (Maisine ™) PEO 301 FP115.9  33.1 114.1  32.6 BHA 1.1  0.3 1.1  0.3 BHT 0.4  0.1 0.4  0.1Oxycodone HCl 10.6  3.0 15.9  4.5 TOTAL 350.0 100.0% 350.0 100.0% RatioPEO:Maisine ™ 35-1 1:1.9  1:1.9 Ratio API:PEO 1:10.9 1:7.2 Dosage 20 mg30 mg Component Mass (mg) % weight Mass (mg) % weight Glycerylmonolinoleate 215.0  61.4 208.1  59.4 (Maisine ™) PEO 301 FP 112.3  32.1108.6  31.0 BHA 1.1  0.3 1.1  0.3 BHT 0.4  0.1 0.4  0.1 Oxycodone HCl21.2  6.1 31.8  9.1 TOTAL 350.0 100.0% 350.0 100.0% Ratio PEO:Maisine ™35-1 1:1.9  1:1.9 Ratio API:PEO 1:5.3  1:3.4 Dosage 40 mg Component Mass(mg) % weight Glyceryl monolinoleate 201.1  57.5 (Maisine ™) PEO 301 FP105.0  30.0 BHA 1.1  0.31 BHT 0.4  0.13 Oxycodone HCl 42.4  12.1 TOTAL350.0 100.0% Ratio PEO:Maisine ™ 35-1 1:1.9  Ratio API:PEO 1:2.5 

What is claimed is:
 1. A method for treating, reducing the symptoms of,or retarding the onset of pain comprising administering to a subject inneed thereof of an oral pharmaceutical composition comprising about 35%to about 70% by mass glyceryl monolinoleate, about 20% to about 50% bymass polyethylene oxide having a molecular weight (M_(v)) of about1,000,000 to about 7,000,000, and oxycodone or a salt thereof.
 2. Themethod of claim 1, wherein the pharmaceutical composition comprises: (a)about 50% to about 70% by mass glyceryl monolinoleate; (b) about 25% toabout 40% by mass polyethylene oxide having a molecular weight (M_(v))of about 1,000,000 to about 7,000,000; and (c) about 1% to about 20% bymass of oxycodone or a salt thereof.
 3. The method of claim 1, whereinthe pain arises from one or more of diabetic neuropathy, chronicarthritis, osteoarthritis, rheumatoid arthritis, acute tendonitis,bursitis, headaches, migraines, chronic neuropathies, shingles,premenstrual symptoms, sports injuries, malignancy, radiculopathy,sciatica/sciatic pain, sarcoidosis, necrobiosis, lipoidica, granulomaannulare, trauma, cancer, or a combination thereof.
 4. The method ofclaim 1, wherein upon ingestion by the subject the composition iscapable of achieving one or more of the following pharmacokineticparameters: (a) a mean plasma oxycodone T_(max) of about 1 hours toabout 8 hours; (b) a mean plasma oxycodone C_(max) of about 10 ng/mL toabout 150 ng/mL; or (c) a mean plasma oxycodone AUC_(0→∞) of about 100h·ng/mL to about 1000 h·ng/mL.
 5. The method of claim 1, wherein thepharmaceutical composition forms an abuse deterrent elastic semi-solidcomposition after having been heated at a temperature of about 50° C. toabout 80° C. for about 10 min to about 180 min, and cooled to roomtemperature.
 6. The method of claim 1, wherein the pharmaceuticalcomposition comprises a mass ratio of polyethylene oxide to glycerylmonolinoleate of about 1:2.
 7. The method of claim 1, wherein thepharmaceutical composition comprises a mass ratio range of oxycodone topolyethylene oxide of about 1:1 to about 1:20.
 8. The method of claim 1,wherein the oxycodone comprises about 0.5% to about 20% of thecomposition by mass.
 9. The method of claim 1, wherein the compositionfurther comprises one or more antioxidants.
 10. The method of claim 9,wherein the antioxidant comprises about 0.05% to about 0.5% of thecomposition by mass.
 11. The method of claim 1, wherein the polyethyleneoxide comprises a polyethylene oxide having an average molecular weight(M_(v)) of about 4,000,000.
 12. The method of claim 1, wherein theoxycodone comprises about 5 mg, about 10 mg, about 15 mg, about 20 mg,about 30 mg, or about 40 mg of oxycodone hydrochloride.
 13. The methodof claim 1, wherein the composition is encapsulated in a capsule.
 14. Amethod for delivering about 40 mg of oxycodone comprising administeringto a subject one or more pharmaceutical dosage forms comprising about35% to about 70% by mass glyceryl monolinoleate, about 20% to about 50%by mass polyethylene oxide having a molecular weight (M_(v)) of about1,000,000 to about 7,000,000, and oxycodone or a salt thereof, themethod capable of achieving one or more of the following pharmacokineticparameters following ingestion by the subject: (a) a mean plasmaoxycodone T_(max) of about 4.5 hours to about 5.0 hours; (b) a meanplasma oxycodone C_(max) of about 40 ng/mL to about 65 ng/mL; (c) a meanplasma oxycodone AUC_(0→τ) of about 400 h·ng/mL to about 500 h·ng/mL;(d) a mean plasma oxycodone AUC_(0→∞) of about 400·h·ng/mL to about 500h·ng/mL; (e) a mean oxycodone half-life (t_(1/2)) of about 4.4 hours toabout 4.6 hours; or (f) a mean oxycodone overall elimination rateconstant (λ_(z)) of about 0.14 h⁻¹ to about 0.17 h⁻¹.
 15. The method ofclaim 14, wherein the pharmaceutical dosage form exhibits an in vitrodissolution rate at pH 1.2 of about 50% after about 90 minutes.
 16. Themethod of claim 14, wherein the dosage form comprises a capsuleencapsulating an abuse deterrent elastic semi-solid compositioncomprising: (a) about 35% to about 70% by mass glyceryl monolinoleate;(b) about 20% to about 50% by mass polyethylene oxide having a molecularweight (M_(v)) of about 1,000,000 to about 7,000,000; and (c) about 1%to about 20% by mass of oxycodone or a salt thereof; and the dosage formhaving been heated to about 50° C. to about 80° C. for about 10 min toabout 180 min, and cooled to room temperature.
 17. A method forinhibiting extraction of oxycodone from a pharmaceutical composition,the method comprising: administering a dosage form comprising a capsuleencapsulating a: (a) about 35% to about 70% by mass glycerylmonolinoleate; (b) about 20% to about 50% by mass polyethylene oxidecomprising having a molecular weight (M_(v)) of about 1,000,000 to about7,000,000; and (c) about 1% to about 20% by mass of oxycodone or a saltthereof; and the dosage form having been heated to about 50° C. to about80° C. for about 10 min to about 180 min, and cooled to roomtemperature; and wherein the dosage form is resistant to crushing,grating, grinding, cutting, solvation, or dissolution in water oralcohol.
 18. The method of claim 17, wherein the capsule comprises acoated soft capsule.